EP3197460A1 - Dermocosmetic or pharmaceutical use of a composition containing at least one inhibitor of certain chemokines - Google Patents

Dermocosmetic or pharmaceutical use of a composition containing at least one inhibitor of certain chemokines

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Publication number
EP3197460A1
EP3197460A1 EP15788100.4A EP15788100A EP3197460A1 EP 3197460 A1 EP3197460 A1 EP 3197460A1 EP 15788100 A EP15788100 A EP 15788100A EP 3197460 A1 EP3197460 A1 EP 3197460A1
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EP
European Patent Office
Prior art keywords
use according
formula
composition used
group
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP15788100.4A
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German (de)
French (fr)
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EP3197460B1 (en
Inventor
Philippe Bernard
Dayana ABBOUD
Jean-Luc Galzi
Nelly FROSSARD
Christelle Pillard
Quoc Tuan DO
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Centre National de la Recherche Scientifique CNRS
Universite de Strasbourg
Greenpharma SAS
Original Assignee
Centre National de la Recherche Scientifique CNRS
Universite de Strasbourg
Greenpharma SAS
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Publication of EP3197460A1 publication Critical patent/EP3197460A1/en
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to the use of certain chemo-attractant cytokine inhibiting derivatives (generally referred to as chemokines) in cosmetic or pharmaceutical compositions. Specifically, it relates to novel applications of said salicylic or nicotinic acid derivatives for treating chronic inflammatory diseases; in this respect, chronic inflammatory diseases such as dermatitis (acne, atopic dermatitis, psoriasis, eczema, dry skin with atopic tendency, redness, etc.) or internal diseases such as Crohn's disease, asthma, allergic asthma and allergic rhinitis.
  • chronic inflammatory diseases such as dermatitis (acne, atopic dermatitis, psoriasis, eczema, dry skin with atopic tendency, redness, etc.
  • internal diseases such as Crohn's disease, asthma, allergic asthma and allergic rhinitis.
  • Crohn's disease is a chronic inflammatory bowel disease.
  • the publication of Grip 0. and Janciauskiene S. (Atorvastatin reduces plasma levels of chemokine (CXCL10) in patients with Crohn's disease, PloS One, 2009, 4 (5): e5263) shows the importance of chemokines in this pathology.
  • Allergic rhinitis is a chronic disease often associated with chronic dermatoses.
  • An article by Takeuchi S. et al (Changes in Thymus and Activation-Regulated Chemokine (TARC) Associated with Allergen Immunotherapy in Patients with Perennial Allergy Rhinitis, J Investigation Allergol Clin Immunol, 2005, 15 (3), 172-6) shows the involvement of chemokines in this pathology.
  • Dermatoses are conditions of the skin and mucous membranes, which are characterized by unsightly manifestations such as redness and desquamation plaques.
  • Several pathologies are grouped under the denomination of dermatoses. We can mention non-limiting examples, eczema, atopic dermatitis, psoriasis, seborrheic dermatitis or acne. These dermatoses often result from inflammatory phenomena and immune disorders.
  • atopic dermatitis In the case of atopic dermatitis, lesions are characterized by severe cutaneous dryness and inflammatory lesions: erythematous, papular, vesicular, squamous and very itchy eruptions (itching). Histologically, atopic dermatitis, like many dermatoses, is characterized by an infiltration of lymphocytes, monocytes and eosinophilic polynuclear cells around small vessels and capillaries. Biochemically, it has been shown that chemokines are strongly implicated in dermatosis and in chronic inflammatory diseases in general.
  • Chemokines are a family of small, mostly soluble, 8-14 kD proteins. Their most studied function is the attraction and control of the activation state of the cells of the immune system. Some chemokines have proven to be good therapeutic targets for treating internal and external chronic inflammatory diseases in humans or animals.
  • the present invention highlights novel cosmetic, pharmaceutical and veterinary applications of certain effective agents for directly inhibiting chemokines and treating chronic inflammatory diseases in humans or animals.
  • the generic term "pharmaceutical” is used to define both a product intended for application in humans and a product intended for application in animals.
  • the invention relates to the use of a dermo-cosmetic or pharmaceutical composition for treating inflammatory diseases of human or animal skin, characterized in that said composition contains, in a pharmaceutically acceptable vehicle, an effective amount of at least an active agent corresponding to the general formula (I):
  • X represents a group -CH- or a nitrogen atom
  • R represents a (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl group, in which one or more -CH 2 - groups may be replaced by -O- or may be substituted with one or more radicals selected from the radicals ( Ci-C 6 ) alkyl, hydroxy and alkoxy, said compound of formula (I) may be in the form of a basic or acid addition salt.
  • the active agent is in the form of an acid addition salt
  • said acid is advantageously chosen from the group formed by the acids hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric,. tartaric, maleic, citric, ascorbic, methane- or ethane-sulphonic and camphoric.
  • the active agent is in the form of a basic addition salt
  • said base is advantageously chosen from the group formed by sodium hydroxide or potassium, triethylamine and t-butylamine.
  • the compounds of formula (I) can have one or more asymmetric center (s) and can then be isolated in optically active form or in the form of their racemic mixture.
  • Methods for obtaining optically active forms for example by resolution of a racemic form or by synthesis using racemic starting materials, are well known to those skilled in the art.
  • alkyl denotes a linear or branched hydrocarbon radical advantageously having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl pentyl, neopentyl, n-hexyl.
  • the alkyl groups may be substituted by one or more hydroxyl groups and / or by one or more alkoxy groups as defined below.
  • cycloalkyl denotes a cyclic hydrocarbon system comprising from 3 to 6 carbon atoms and which may be mono- or poly-cyclic. In particular, cyclopropyl and cyclohexyl radicals may be mentioned.
  • alkoxy groups correspond to the linear or branched alkyl groups defined above connected via an -O- (ether) bond. We prefer everything especially the methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy and s-pentoxy groups.
  • the alkoxy groups may be substituted by an alkyl group as defined above or by another alkoxy group.
  • the invention particularly relates to a use which uses a composition comprising at least one compound of formula (I) as an active agent for treating inflammatory diseases of the skin.
  • a composition comprising at least one compound of formula (I) as an active agent for treating inflammatory diseases of the skin.
  • Such a composition may also comprise at least one active agent other than those of formula (I) to exert at least one complementary or synergistic action.
  • the composition used according to the invention is in the form of capsules, cream, gel, lotion, milk, emulsion, biphasic emulsion, O / W or W / O emulsion, emulsion. triphasic, solution, ointment, body oil, shampoo, soap, lip stick, stick and pencil for make-up, mask, nano-capsule, liposome, transdermal patches for topical applications.
  • composition used according to the invention may comprise suitable excipients, such as cellulose esters, or other gelling agents such as carboxylic acid polymer "Carbopol ®” and guar gum, for example.
  • suitable excipients such as cellulose esters, or other gelling agents such as carboxylic acid polymer "Carbopol ®” and guar gum, for example.
  • compositions used according to the invention have good stability and can be stored for the time necessary for use at temperatures between 0 and 50.degree. sedimentation of constituents or phase separation.
  • the active agent (s) is (are) put in place in encapsulation means chosen from group formed by microspheres, liposomes, glycospheres, chylomicrons, macro-micro-, and nanoparticles, macro-, micro- and nanocapsules.
  • the active agent (s) is (are) absorbed (s) or adsorbed (s) on polymers. powdery organic, talcs, bentonite or other powdery mineral supports.
  • the active agent (s) of formula (I) constitutes (s) from 0.01% to 5% by weight. % by weight relative to the total weight of the composition.
  • the active agent (s) of formula (I) is (or are) in encapsulated form and constitutes nt), preferably from 0.5 to 5% by weight relative to the total weight of the composition.
  • the subject of the invention is, in particular, the use of a composition as previously described for preventing and / or treating inflammatory diseases. chronic either internal, such as Crohn's disease, asthma, allergic asthma and allergic rhinitis, or external related to seborrheic, acne, inflammatory and immunological activities; such a composition may especially be used to prevent and / or treat dermatoses, psoriasis, atopic dermatitis, as well as inflammatory conditions of the cutaneous or hair systems inducing itching, irritation, chronic redness or functional disorders of the fragility capillary.
  • a composition as previously described for preventing and / or treating inflammatory diseases. chronic either internal, such as Crohn's disease, asthma, allergic asthma and allergic rhinitis, or external related to seborrheic, acne, inflammatory and immunological activities; such a composition may especially be used to prevent and / or treat dermatoses, psoriasis, atopic dermatitis, as well as inflammatory conditions of the cutaneous
  • the invention has therefore demonstrated the possibility of using the compounds of formula (I) as active agent (s). These compounds have very good properties for inhibiting certain chemokines, such as CCL22 and / or CCL17.
  • the present invention therefore aims precisely to propose a new pharmaceutical, dermatological or cosmetic use implementing compositions capable of treating internal and external chronic inflammatory diseases such as skin that is irritated, injured or sensitized by external or internal aggression, in general, and dermatoses, in particular.
  • the subject of the present invention is a cosmetic use of at least one compound of formula (I) for inhibiting the chemokine CCL22 and / or CCL17, for soothing dry skin with atopic tendency and / or for improving and / or strengthening the skin. hydration of the skin. It therefore concerns applications to treat chronic inflammatory conditions such as Crohn's disease, allergic rhinitis, asthma, dermatoses such as atopic dermatitis, eczema and psoriasis.
  • the derivatives of formula (I) capable of inhibiting the chemokine CCL22 and / or CCL17 may be administered topically but they can also be administered orally. These derivatives can be used as such, in liquid or powder form, unpurified or purified.
  • the derivatives of formula (I) capable of inhibiting chemokines may, in the compositions used, be associated with one another or with other compounds that complement or indeed synergize this effect.
  • the protective activity of the derivatives of formula (I) with respect to free radicals and UV is interesting in the hair field, especially in the case of combination with substances facilitating the good condition of the scalp and hair . It is possible to mention associations with mucopolysaccharides, minerals, vitamins, ceramides, vegetable oils, antiradical substances, U.V. filters, flower acids or fruit acids.
  • the restorative activity of compounds of formula (I) capable of inhibiting chemokines is particularly advantageous when they are associated with substances having a healing effect such as proteins, hyaluronic acid, amino acids, or with anti-inflammatory substances, anti-aging, after-sun anti-acne or anti-dermatosis.
  • compositions used according to the invention are particularly suitable for topical application for preventing and / or treating numerous skin disorders, especially as a repairing and / or protective agent for the skin and the hair system, such as the hair, for to fight against external aggressions related to pollution, sun, oxidative stress, aging and skin pathologies leading to dysfunction of homeostasis of the epidermis or hair.
  • These cosmetic compositions implemented according to the invention may also take the form of lotions or solutions in which the compounds of formula (I) are in encapsulated form, for example in microspheres. These microspheres may, for example, consist of fat, agar and water.
  • the active agents may also be incorporated into liposome, glycosphere-type vectors in chylomicrons, macro-, micro-, nanoparticles as well as macro-, micro- and nanocapsules and also be adsorbed onto powdery organic polymers, talcs , bentonites and other mineral supports.
  • the compounds of formula (I) may be mixed with the excipients generally used in cosmetics.
  • the cosmetic compositions used according to the invention may therefore contain additives or adjuvants customary in cosmetology, such as, for example, antibacterial agents or perfumes, but also extraction and / or synthetic lipids, gelling and viscosity polymers, surfactants, emulsifiers, hydro- or liposoluble active agents, plant extracts, tissue extracts, marine extracts, or synthetic actives.
  • the dermo-cosmetic or pharmaceutical use of the compounds of formula (I) includes all skincare and skin care products, including sun, protective and tanning products, anti-aging, anti-seborrhoeic, tonic products, products that improve the appearance of the skin, including acne treatment, skin rash treatment, scalp treatment and hair loss.
  • the cosmetic compositions used according to the present invention may also comprise other agents complementary active ingredients chosen for their action, for example for sunscreen, anti-wrinkle effect, antiradical and antioxidant activity, anti-irritant activity, cellular nutrition, cellular respiration, hydration and cellular regeneration , anti-seborrhoeic treatments, as well as other active agents having an action on the skin tonicity and the protection of the hair.
  • agents complementary active ingredients chosen for their action, for example for sunscreen, anti-wrinkle effect, antiradical and antioxidant activity, anti-irritant activity, cellular nutrition, cellular respiration, hydration and cellular regeneration , anti-seborrhoeic treatments, as well as other active agents having an action on the skin tonicity and the protection of the hair.
  • the cosmetic compositions used according to the present invention are, preferably, to be used daily by applying them one or more times per day.
  • compositions used according to the present invention are very well tolerated, they have no phototoxicity and their application to the skin for prolonged periods of time does not imply any systemic effect.
  • the invention also relates to the use of compounds of formula (I) for the preparation of pharmaceutical compositions having an anti-inflammatory and / or dermoprotective activity.
  • These compositions are useful for preventing and / or treating in particular dermatological diseases related to seborrheic, acneic, inflammatory and immunological activities.
  • the invention thus relates to the use of a pharmaceutical, dermatological or cosmetic composition containing compounds of. formula (I) capable of inhibiting certain chemokines, intended to prevent and / or treat pathologies and disorders resulting from:
  • dermatoses such as psoriasis, acne and atopic dermatitis
  • Examples 1 to 3 illustrate a process for the preparation of compounds of formula (I) capable of inhibiting the CCL22 chemokine according to the invention.
  • the starting materials are commercially available or can be synthesized by conventional methods known to those skilled in the art.
  • the reaction medium is stirred for 5 hours at room temperature and then hydrolysed with 30 ml of water. It is extracted with dichloromethane (3 times 30 mL). The combined organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude is purified by chromatography on silica gel (petroleum ether / ethyl acetate 9/1) to give 1.16 g (yield: 87%) of the expected product coded 1 in the form of a colorless oil.
  • Example 4 demonstrates the technical protocol for recording the effects of the products according to the invention on the chemokines.
  • the cDNA that allows its expression is cloned into the plasmid pIRES (ClonTech) in fusion with the GFP protein, according to Vollmer et al. (1999), which makes it easy to measure the expression of the EGFP-CCR chimeric receptor.
  • the HEK 293 (ATCC) cells are cultured in MEM minimum essential medium (Invitrogen) in the presence of 10% fetal calf serum (Gibco-BRL), 100 U / mL penicillin (Invitrogen), 100 ⁇ g / mL streptomycin (Invitrogen) ) and 2 mM L-glutamine (Invitrogen) at 37 ° C in atmosphere saturated with water and containing 5% CO2.
  • the cells are transfected according to the calcium phosphate precipitate method of Chen and Okayama, 1986, and the cells having incorporated the expression plasmid are selected using 600 ⁇ g / ml of geneticin G-418 (PAA) for 5 weeks.
  • the clones are selected after having been characterized by fluorescence microscopy and fluorescence-assisted cell sorting (FACS) cytometric analysis. Construction of the recombinant protein Gqi5
  • the chimeric protein Gq15 is produced by site-directed mutagenesis of the last 5 amino acids of Gq, which are replaced by their Gi counterparts.
  • the cells expressing the CCR4 receptor are transfected with the plasmid pCNA3.1 in which the cDNA encoding Gq15 was incorporated. Recordings of calcium responses are made the day after transfection.
  • FIG. 1 generally illustrates the results obtained: the addition of chemokine (CK) to cells expressing the chemokine receptor (CR) triggers an intracellular calcium release that is harnessed by the fluorescence change of the Indo-1 calcium probe.
  • CK chemokine
  • CR chemokine receptor
  • the response develops in a few seconds and diminishes with time to reach the return in about 2 minutes for a concentration of 5 to 10 nM of the chemokine CCL22 on HEK 293 cells expressing CCR4. If the test molecules are preincubated with the chemokine [CK + N] and the mixture is added to the cells, a marked decrease in the amplitude of the response is observed if the test molecule is a chemokine neutraligand. . Conversely, when the neutraligand is preincubated with the cells expressing the [CKR + N] receptor, a much smaller decrease in the amplitude of the response is observed.
  • the apparent affinity of the GPN136 molecules is determined by the establishment of a dose-response relationship of the inhibition of the calcium response as presented in FIG. 2 and the results obtained are reported in Table 1.
  • the analysis of the selectivity of the molecules is carried out by measurement of inhibition of the evoked response by other chemokines on their respective receptors and, in FIG. 3, the molecules have been tested on the CCL2 / CCR2, CCL3-5 pairs. / CCR5, CCL17 / CCR4, CCL22 / CCR4, CXCL8 / CXCR8, CXCL10 / CXCR2, CXCL11 / CXCR3, CXCL12 / CXCR4
  • Figure 3 shows the selectivity of CCL22 neutralizers (GPN136 (black bars) and GPN025 (white bars)) on the indicated chemokines and their respective receptors.
  • Figure 4 shows the inhibition of the intrinsic fluorescence of CCL22 by the neutraligand GPN 136 (white squares).
  • the CCR4 receptor antagonist, C-021 does not show a decrease in tryptophan fluorescence (black squares).
  • Example 5 shows how non-cytotoxic active candidates are selected.
  • the activity of the GPN 136 molecule was evaluated in a human keratinocyte migration test carried out according to a cell-wall healing test. It is indeed known that, in these chronic pathologies, a significant migration of cells can promote the formation of pruritus, one of the manifestations of dermatitis.
  • the immortalized human keratinocytes obtained from DKFZ (Heidelberg, Germany) are cultured in Eagle-modified Dulbecco's medium (DMEM, InVitrogen) supplemented with 10% fetal calf serum (Gibco-BRL) and 100 U / ml penicillin ( Invitrogen), 100 ⁇ g / ml streptomycin (Invitrogen) and 2 mM glutamine (Invitrogen) at 37 ° C and 5% CO2.
  • DMEM Eagle-modified Dulbecco's medium
  • Invitrogen 10% fetal calf serum
  • Invitrogen 100 U / ml penicillin
  • Invitrogen 100 ⁇ g / ml streptomycin
  • 2 mM glutamine Invitrogen
  • the medium is then replaced to remove the cells and their debris and the culture is continued under different experimental conditions: (i) without any addition, (ii) addition of 100 ng / ml of CCL22 and (iii) addition of a mixture containing 100 ng / ml of CCL22 and the molecule to be tested, for example GPN 136.
  • the effect of single molecules is also recorded in different wells. In order to block cell proliferation, each well receives a dose of 1 g / ml of mytomycin (Sigma-Aldrich).
  • the culture plates are placed in the IncuCyte apparatus which records the growth of the cell layer by imaging transmitted under cell culture conditions (37 ° C, 5% CO2, saturated atmosphere of water) for 72 hours. Phase contrast images are acquired every 2 hours. Healing is defined (quantified) as the ratio of scar width at time t to time 0. The experiment is repeated three times per condition. The results obtained are reported in Figure 5.
  • Figure 5 shows the migration of human keratinocytes under the effect of GNP136; it shows photographs of human Hacat cell carpets after injury at time 0 and after 72h of culture in the presence of excipient alone (DMSO, panel 1), CCL22 and excipient (CCL22 + D SO, panel 2) and CCL22 and GPN 136 (CCL22 + GPN136, panel 3)
  • Figure 6 shows the effect of the added GPN025 molecule on day 10 after injury to the Hacat cell mat. It is noted that the cells appear to have formed syncytia after 72 hours of incubation. It is impossible to distinguish the outlines. The molecule GPN025 damages Hacat cells. This effect is quantified in the metabolic activity experiment shown in Figure 6.
  • the metabolic activity test is a colorimetric test (WST-1 assay - Ozyme) based on the measurement of the activity of the mitochondrial enzyme succinate-tetrazolium reductase cleaving the tetrazolium salt WST-1 ((4- [3- (4-Iodophenyl) -2- (4-nitrophenyl) -2H-5-tetrazoloyl-1,3-benzenesulfonate)) to a water-soluble derivative, formazan which is a light-absorbing dye in the 420-480 nm window.
  • the HaCat cells are distributed at a rate of 200,000 cells per well in a 24-well culture plate, in a final volume of 500 ⁇ l.
  • Figure 7 shows the cytotoxic activity of GPN136 and GPN025
  • In vitro cytotoxic activity HaCat cell cultures are treated with different molecule concentrations: 0.3 ⁇ (dark gray bars) 10 ⁇ (light gray bars) or 30 ⁇ (white bars) GPN 136 and GPN 025 molecules. Mitochondial formazan-reductase enzyme activity is recorded using WST-1 chromogenic substrate which turns into colored product, formazan, detected at 450 nm. As shown in FIG. 7, the GPN 136 molecule does not affect the enzymatic activity. In contrast, the GPN 025 molecule reduces in a dependent and significantly cellular metabolism, thus revealing a cytotoxic effect of GPN 025.
  • This example presents a formulation of the composition according to the invention.
  • This composition is applied every day for 1 month on the skin of the face of a 20-year-old man suffering from atopic dermatitis on the entire face; this application is made at a rate of about 2 g / day for the complete face. The total disappearance of the inflammation zones at the end of the treatment is observed.
  • ingredients with anti-inflammatory properties commonly used in cosmetic products in particular nicotinamide (1 to 4%), beta-glycyrrhetinic acid (0.01 to 1%), alpha bisabolol (0.1 to 1%);
  • a bacterial anti-adhesion agent to limit the adhesion and proliferation of Staphylococcus aureus such as Solabia Teflose® composed of propanediol, rhamnose, glucose and glucuronic acid (2-4%);
  • a safflower or evening primrose vegetable oil stabilized in a ceramide-like form such as "Omega ⁇ Ceramide® Safflower” and "Omega 6 Ceramide® Evening primrose” from Solabia to improve cell cohesion (0.1 to 1%)

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Abstract

The invention relates to the cosmetic or pharmaceutical use of a composition containing a derivative of nicotinic or salicylic acid that inhibits chemokines, in order to prevent or treat internal and/or external chronic inflammatory disorders.

Description

UTILISATION DERMOCOSMETIQUE OU PHARMACEUTIQUE D'UNE COMPOSITION CONTENANT AU MOINS UN INHIBITEUR DE CERTAINES DERMOCOSMETIC OR PHARMACEUTICAL USE OF A COMPOSITION CONTAINING AT LEAST ONE INHIBITOR OF CERTAIN
CHIMIOKINES Chemokines
La présente invention concerne l'utilisation de certains dérivés inhibant les cytokines chimio-attractantes (généralement appelées chimiokines) , dans des compositions cosmétiques ou pharmaceutiques. Plus précisément, elle se rapporte à de nouvelles applications desdits dérivés de l'acide salicylique ou nicotinique pour traiter des maladies inflammatoires chroniques ; on peut citer à cet égard, les maladies inflammatoires chroniques externes comme les dermatoses (acné, dermatite atopique, psoriasis, eczéma, peau sèche à tendance atopique, rougeurs...) ou internes comme la maladie de Crohn, l'asthme, l'asthme allergique et la rhinite allergique.  The present invention relates to the use of certain chemo-attractant cytokine inhibiting derivatives (generally referred to as chemokines) in cosmetic or pharmaceutical compositions. Specifically, it relates to novel applications of said salicylic or nicotinic acid derivatives for treating chronic inflammatory diseases; in this respect, chronic inflammatory diseases such as dermatitis (acne, atopic dermatitis, psoriasis, eczema, dry skin with atopic tendency, redness, etc.) or internal diseases such as Crohn's disease, asthma, allergic asthma and allergic rhinitis.
La maladie de Crohn est une maladie inflammatoire chronique de l'intestin. La publication de Grip 0. et Janciauskiene S. (Atorvastatin reduces plasma levels of chemokine (CXCL10) in patients with Crohn 's disease, PloS One, 2009, 4(5):e5263) montre l'importance des chimiokines dans cette pathologie.  Crohn's disease is a chronic inflammatory bowel disease. The publication of Grip 0. and Janciauskiene S. (Atorvastatin reduces plasma levels of chemokine (CXCL10) in patients with Crohn's disease, PloS One, 2009, 4 (5): e5263) shows the importance of chemokines in this pathology.
La rhinite allergique est une maladie chronique souvent attachée aux dermatoses chroniques. Un article de Takeuchi S. et al (Changes in thymus- and activation- regulated chemokine (TARC) associated with allergen immunotherapy in patients with perennial allergie rhinitis. J Investig Allergol Clin Immunol, 2005, 15(3), 172-6) montre l'implication des chimiokines dans cette pathologie.  Allergic rhinitis is a chronic disease often associated with chronic dermatoses. An article by Takeuchi S. et al (Changes in Thymus and Activation-Regulated Chemokine (TARC) Associated with Allergen Immunotherapy in Patients with Perennial Allergy Rhinitis, J Investigation Allergol Clin Immunol, 2005, 15 (3), 172-6) shows the involvement of chemokines in this pathology.
Les dermatoses sont des affections de la peau et des muqueuses, qui se caractérisent par des manifestations inesthétiques comme des rougeurs et des plaques de desquamation. Plusieurs pathologies sont regroupées sous la dénomination de dermatoses. On peut citer, à titre d'exemples non limitatifs, l'eczéma, la dermatite atopique, le psoriasis, les dermites séborrhéiques ou encore l'acné. Ces dermatoses résultent bien souvent de phénomènes inflammatoires et de désordres immunitaires. Dermatoses are conditions of the skin and mucous membranes, which are characterized by unsightly manifestations such as redness and desquamation plaques. Several pathologies are grouped under the denomination of dermatoses. We can mention non-limiting examples, eczema, atopic dermatitis, psoriasis, seborrheic dermatitis or acne. These dermatoses often result from inflammatory phenomena and immune disorders.
Dans le cas de la dermatite atopique, les lésions se caractérisent par une sécheresse cutanée importante et par des lésions inflammatoires : éruptions érythémateuses papuleuses, vésiculeuses, squameuses et très prurigineuses (démangeaisons) . Sur le plan histologique, la dermatite atopique se caractérise, comme bien des dermatoses, par une infiltration de lymphocytes, monocytes et de polynucléaires éosinophiles autour des petits vaisseaux et des capillaires. Sur le plan biochimique, il a été montré que les chimiokines sont fortement impliquées dans les dermatoses et dans les maladies inflammatoires chroniques en général. A titre d'exemple, la publication de Folsgaard et al (Cord blood Th2-related chemokine CCL22 levels associate with elevated total-IgE during preschool âge, Clin. Exp. Allergy, 2012, 42(11), 1596-603) met en évidence l'importance de la chimiokine CCL22 dans la dermatite atopique. Une autre publication de Hashimoto et al (Macrophage-derived chemokine (MDC) /CCL22 produced by monocyte derived dendritic cells reflects the disease activity in patients with atopic dermatitis, Journal of Dermatological Science, 2006, 44(2), 93-9) met en évidence l'importance de la même chimiokine CCL22 dans les maladies de la peau.  In the case of atopic dermatitis, lesions are characterized by severe cutaneous dryness and inflammatory lesions: erythematous, papular, vesicular, squamous and very itchy eruptions (itching). Histologically, atopic dermatitis, like many dermatoses, is characterized by an infiltration of lymphocytes, monocytes and eosinophilic polynuclear cells around small vessels and capillaries. Biochemically, it has been shown that chemokines are strongly implicated in dermatosis and in chronic inflammatory diseases in general. For example, the publication of Folsgaard et al (Cord blood Th2-related chemokine CCL22 levels associated with elevated total-IgE during preschool age, Clin, Exp Allergy, 2012, 42 (11), 1596-603) puts evidence of the importance of the chemokine CCL22 in atopic dermatitis. Another publication by Hashimoto et al (Macrophage-derived chemokine (MDC) / CCL22 produced by monocyte derived dendritic cells reflects the disease activity in patients with atopic dermatitis, Journal of Dermatological Science, 2006, 44 (2), 93-9) states that highlight the importance of the same chemokine CCL22 in skin diseases.
Les chimiokines sont une famille de petites protéines, majoritairement solubles, de 8-14 kD. Leur fonction la plus étudiée est l'attraction et le contrôle de l'état d'activation des cellules du système immunitaire. Certaines chimiokines s'avèrent être de bonnes cibles thérapeutiques pour traiter les maladies inflammatoires chroniques internes et externes chez l'homme ou l'animal. La présente invention met en évidence de nouvelles applications cosmétiques, pharmaceutiques et vétérinaires de certains agents efficaces pour inhiber directement les chimiokines et traiter les maladies inflammatoires chroniques chez l'homme ou l'animal. Dans cette demande de brevet, on utilise le terme générique « pharmaceutique » pour définir aussi bien un produit destiné à une application chez l'homme qu'un produit destiné à une application chez 1' animal . Chemokines are a family of small, mostly soluble, 8-14 kD proteins. Their most studied function is the attraction and control of the activation state of the cells of the immune system. Some chemokines have proven to be good therapeutic targets for treating internal and external chronic inflammatory diseases in humans or animals. The present invention highlights novel cosmetic, pharmaceutical and veterinary applications of certain effective agents for directly inhibiting chemokines and treating chronic inflammatory diseases in humans or animals. In this patent application, the generic term "pharmaceutical" is used to define both a product intended for application in humans and a product intended for application in animals.
L'invention concerne l'utilisation d'une composition dermo-cosmétique ou pharmaceutique destinée à traiter des maladies inflammatoires de la peau humaine ou animale, caractérisée en ce que ladite composition contient, dans un véhicule pharmaceutiquement acceptable, une quantité efficace d'au moins un agent actif répondant à la formule générale (I) :  The invention relates to the use of a dermo-cosmetic or pharmaceutical composition for treating inflammatory diseases of human or animal skin, characterized in that said composition contains, in a pharmaceutically acceptable vehicle, an effective amount of at least an active agent corresponding to the general formula (I):
formule dans laquelle : formula in which:
X représente un groupe -CH- ou un atome d' azote ;  X represents a group -CH- or a nitrogen atom;
R représente un groupe (Ci-C6) alkyle, (C3-C6) cycloalkyle, dans lesquels un ou plusieurs groupements -CH2- peuvent être remplacés par -0- ou peuvent être substitués par un ou plusieurs radicaux choisis par les radicaux (Ci-C6) alkyle, hydroxy et alcoxy, ledit composé de formule (I) pouvant être sous forme d'un sel d'addition basique ou acide. R represents a (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl group, in which one or more -CH 2 - groups may be replaced by -O- or may be substituted with one or more radicals selected from the radicals ( Ci-C 6 ) alkyl, hydroxy and alkoxy, said compound of formula (I) may be in the form of a basic or acid addition salt.
Lorsque dans la composition mise en œuvre dans l'utilisation selon l'invention, l'agent actif est sous la forme d'un sel d'addition acide, ledit acide est avantageusement choisi dans le groupe formé par les acides chlorhydrique, bromhydrique, sulfurique, phosphorique, acétique, trifluoroacétique, lactique, pyruvique, malonique, succinique, glutarique, fumarique, . tartrique, maléique, citrique, ascorbique, méthane- ou éthane-sul fonique et camphorique . When in the composition used in the use according to the invention, the active agent is in the form of an acid addition salt, said acid is advantageously chosen from the group formed by the acids hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric,. tartaric, maleic, citric, ascorbic, methane- or ethane-sulphonic and camphoric.
Lorsque, dans la composition mise en œuvre dans l'utilisation selon l'invention, l'agent actif est sous la forme d'un sel d'addition basique, ladite base est avantageusement choisie dans le groupe formé par l'hydroxyde de sodium ou de potassium, la triéthylamine et la tertiobutylamine .  When, in the composition used in the use according to the invention, the active agent is in the form of a basic addition salt, said base is advantageously chosen from the group formed by sodium hydroxide or potassium, triethylamine and t-butylamine.
Les composés de formule (I) peuvent posséder un ou plusieurs centre (s) asymétrique ( s ) et peuvent alors être isolés sous une forme optiquement active ou sous forme de leur mélange racémique. Les méthodes permettant d'obtenir des formes optiquement actives, par exemple par résolution d'une forme racémique ou par synthèse utilisant des produits de départ racémiques, sont bien connues de l'homme de l'art.  The compounds of formula (I) can have one or more asymmetric center (s) and can then be isolated in optically active form or in the form of their racemic mixture. Methods for obtaining optically active forms, for example by resolution of a racemic form or by synthesis using racemic starting materials, are well known to those skilled in the art.
Pour la définition des composés de formule (I), le terme « alkyle » désigne un radical hydrocarboné linéaire ou ramifié ayant avantageusement de 1 à 6 atomes de carbone, tels que méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, tert-butyle, pentyle, néopentyle, n-hexyle. Les groupes alkyle peuvent être substitués par un ou plusieurs groupements hydroxyle et/ou par un ou plusieurs groupements alcoxy tel que défini ci-après.  For the definition of compounds of formula (I), the term "alkyl" denotes a linear or branched hydrocarbon radical advantageously having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl pentyl, neopentyl, n-hexyl. The alkyl groups may be substituted by one or more hydroxyl groups and / or by one or more alkoxy groups as defined below.
Le terme « cycloalkyle » désigne un système hydrocarboné cyclique, comprenant de 3 à 6 atomes de carbone et pouvant être mono- ou poly-cyclique . On peut citer notamment les radicaux cyclopropyle et cyclohexyle.  The term "cycloalkyl" denotes a cyclic hydrocarbon system comprising from 3 to 6 carbon atoms and which may be mono- or poly-cyclic. In particular, cyclopropyl and cyclohexyl radicals may be mentioned.
Les groupes « alcoxy » correspondent aux groupes alkyle linéaires ou ramifiés définis ci-dessus reliés par l'intermédiaire d'une liaison -0- (éther) . On préfère tout particulièrement les groupes méthoxy, éthoxy, n-propyloxy, i-propyloxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy et s- pentoxy. Les groupes alcoxy peuvent être substitués par un groupe alkyle comme défini ci-dessus ou par un autre group alcoxy. The "alkoxy" groups correspond to the linear or branched alkyl groups defined above connected via an -O- (ether) bond. We prefer everything especially the methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy and s-pentoxy groups. The alkoxy groups may be substituted by an alkyl group as defined above or by another alkoxy group.
Parmi les composés de formule (I) utilisables comme agent actif dans les compositions mises en œuvre dans l'utilisation selon l'invention, on peut notamment citer : 2 , 3-dihydroxypropyl 2-hydroxybenzoate (codé GPN000136)  Among the compounds of formula (I) that may be used as active agent in the compositions used in the use according to the invention, mention may be made in particular of: 2,3-dihydroxypropyl 2-hydroxybenzoate (coded GPN000136)
( S) -2 , 3-dihydroxypropyl 2-hydroxybenzoate (référencé (S) -2,3-dihydroxypropyl 2-hydroxybenzoate (referenced
GPS008506) GPS008506)
{R) -2, 3-dihydroxypropyl 2-hydroxybenzoate (référencé  {R) -2,3-dihydroxypropyl 2-hydroxybenzoate (referenced
GPS008505) GPS008505)
2, 3-dihydrpxypropyl 4-hydroxynicotinate et ses isomères dipropylene glycol salicylate et ses isomères  2,3-dihydrpoxypropyl 4-hydroxynicotinate and its isomers dipropylene glycol salicylate and its isomers
propylene glycol salicylate et ses isomères propylene glycol salicylate and its isomers
L'invention concerne notamment une utilisation qui met en œuvre une composition comportant au moins un composé de formule (I) comme agent actif pour traiter des maladies inflammatoires de la peau. Une telle composition peut aussi comporter au moins un agent actif autre que ceux de formule (I) pour exercer au moins une action complémentaire ou synergique .  The invention particularly relates to a use which uses a composition comprising at least one compound of formula (I) as an active agent for treating inflammatory diseases of the skin. Such a composition may also comprise at least one active agent other than those of formula (I) to exert at least one complementary or synergistic action.
Selon un autre aspect de l'invention, la composition mise en œuvre selon l'invention se présente sous forme de gélules, crème, gel, lotion, lait, émulsion, émulsion bi- phasique, émulsion H/E ou E/H, émulsion triphasique, solution, onguent, huile corporelle, shampoing, savon, bâton protecteur des lèvres, bâton et crayon pour maquillage, masque, nano-capsule, liposome, patchs transdermiques pour applications topiques.  According to another aspect of the invention, the composition used according to the invention is in the form of capsules, cream, gel, lotion, milk, emulsion, biphasic emulsion, O / W or W / O emulsion, emulsion. triphasic, solution, ointment, body oil, shampoo, soap, lip stick, stick and pencil for make-up, mask, nano-capsule, liposome, transdermal patches for topical applications.
Sous la forme de gel, la composition mise en œuvre selon l'invention peut comprendre des excipients appropriés, tels que les esters de cellulose, ou d'autres agents gélifiants, tels que le polymère carboxylique « Carbopol® » et la gomme de guar, par exemple. In the gel form, the composition used according to the invention may comprise suitable excipients, such as cellulose esters, or other gelling agents such as carboxylic acid polymer "Carbopol ®" and guar gum, for example.
Sous la forme d'émulsions, les compositions mises en œuvre selon l'invention jouissent d'une bonne stabilité et peuvent être conservées pendant le temps nécessaire pour l'utilisation à des températures comprises entre 0 et 50 °C, sans qu'il y ait sédimentation des constituants ou séparation des phases.  In the form of emulsions, the compositions used according to the invention have good stability and can be stored for the time necessary for use at temperatures between 0 and 50.degree. sedimentation of constituents or phase separation.
Selon un autre aspect de l'invention, dans la composition mise en œuvre selon l'invention, l' (ou les) agent (s) actif (s) est (sont) mis en place dans des moyens d' encapsulation choisis dans le groupe formé par des microsphères, des liposomes, des glycosphères, des chylomicrons , des macro- micro-, et nanoparticules , des macro-, micro- et nanocapsules .  According to another aspect of the invention, in the composition implemented according to the invention, the active agent (s) is (are) put in place in encapsulation means chosen from group formed by microspheres, liposomes, glycospheres, chylomicrons, macro-micro-, and nanoparticles, macro-, micro- and nanocapsules.
Selon un autre aspect de l'invention, dans la composition mise en œuvre selon l'invention, l' (ou les) agent (s) actif (s) est (sont) absorbé (s) ou adsorbé(s) sur des polymères organiques poudreux, des talcs, de la bentonite ou d'autres supports minéraux en poudre.  According to another aspect of the invention, in the composition implemented according to the invention, the active agent (s) is (are) absorbed (s) or adsorbed (s) on polymers. powdery organic, talcs, bentonite or other powdery mineral supports.
Selon un autre aspect de l'invention, dans la composition mise en œuvre selon l'invention, l' (ou les) agent(s) actif(s) de formule (I) constitue (nt ) de 0,01% à 5% en poids par rapport au poids total de la composition.  According to another aspect of the invention, in the composition used according to the invention, the active agent (s) of formula (I) constitutes (s) from 0.01% to 5% by weight. % by weight relative to the total weight of the composition.
Selon un autre aspect de l'invention, dans la composition mise en œuvre selon l'invention, l' (ou les) agent (s) actif (s) de formule (I) est (ou sont) sous forme encapsulée et constitue (nt) , de préférence de 0,5 à 5% en poids par rapport au poids total de la composition.  According to another aspect of the invention, in the composition implemented according to the invention, the active agent (s) of formula (I) is (or are) in encapsulated form and constitutes nt), preferably from 0.5 to 5% by weight relative to the total weight of the composition.
L'invention a , notamment, pour objet l'utilisation d'une composition telle que précédemment décrite pour prévenir et/ou traiter des maladies inflammatoires chroniques soit internes, comme la maladie de Crohn, l'asthme, l'asthme allergique et la rhinite allergique, soit externes liées à des activités séborrhéiques, acnéiques, inflammatoires et immunologiques ; une telle composition peut notamment être utilisée pour prévenir et/ou traiter des dermatoses, le psoriasis, la dermatite atopique, ainsi que des états inflammatoires des systèmes cutanés ou pileux induisant des démangeaisons, des irritations, des rougeurs chroniques ou des troubles fonctionnels de la fragilité capillaire. The subject of the invention is, in particular, the use of a composition as previously described for preventing and / or treating inflammatory diseases. chronic either internal, such as Crohn's disease, asthma, allergic asthma and allergic rhinitis, or external related to seborrheic, acne, inflammatory and immunological activities; such a composition may especially be used to prevent and / or treat dermatoses, psoriasis, atopic dermatitis, as well as inflammatory conditions of the cutaneous or hair systems inducing itching, irritation, chronic redness or functional disorders of the fragility capillary.
L'invention a donc mis en évidence la possibilité d'utiliser les composés de formule (I) comme agent(s) actif (s). Ces composés présentent de très bonnes propriétés pour inhiber certaines chimiokines , comme CCL22 et/ou CCL17.  The invention has therefore demonstrated the possibility of using the compounds of formula (I) as active agent (s). These compounds have very good properties for inhibiting certain chemokines, such as CCL22 and / or CCL17.
La présente invention vise donc précisément à proposer une nouvelle utilisation pharmaceutique, dermatologique ou cosmétique mettant en œuvre des compositions capables de traiter les maladies inflammatoires chroniques internes et externes comme les peaux irritées, lésées ou sensibilisées par des agressions externes ou internes, en général, et des dermatoses, en particulier.  The present invention therefore aims precisely to propose a new pharmaceutical, dermatological or cosmetic use implementing compositions capable of treating internal and external chronic inflammatory diseases such as skin that is irritated, injured or sensitized by external or internal aggression, in general, and dermatoses, in particular.
Ainsi, la présente invention a pour objet une utilisation cosmétique d'au moins un composé de formule (I) pour inhiber la chimiokine CCL22 et/ou CCL17, pour apaiser les peaux sèches à tendance atopique et/ou pour améliorer et/ou renforcer l'hydratation de la peau. Elle concerne donc des applications pour soigner les pathologies chroniques inflammatoires comme la maladie de Crohn, la rhinite allergique, l'asthme, les dermatoses comme la dermatite atopique, l'eczéma et le psoriasis.  Thus, the subject of the present invention is a cosmetic use of at least one compound of formula (I) for inhibiting the chemokine CCL22 and / or CCL17, for soothing dry skin with atopic tendency and / or for improving and / or strengthening the skin. hydration of the skin. It therefore concerns applications to treat chronic inflammatory conditions such as Crohn's disease, allergic rhinitis, asthma, dermatoses such as atopic dermatitis, eczema and psoriasis.
Dans la visée thérapeutique de l'invention, les dérivés de formule (I) capables d'inhiber la chimiokine CCL22 et/ou CCL17 peuvent être administrés par voie topique mais ils peuvent aussi être administrés par voie orale. Ces dérivés peuvent être utilisés tels quels, sous forme liquide ou en poudre, non purifiés ou purifiés. In the therapeutic aim of the invention, the derivatives of formula (I) capable of inhibiting the chemokine CCL22 and / or CCL17 may be administered topically but they can also be administered orally. These derivatives can be used as such, in liquid or powder form, unpurified or purified.
Les dérivés de formule (I) capables d'inhiber les chimiokines peuvent, dans les compositions mises en œuvre, être associés entres eux ou avec d'autres composés venant compléter l'effet voire synergiser cet effet. L'activité protectrice des dérivés, de formule (I) vis-à-vis des radicaux libres et des UV est intéressante dans le domaine capillaire, notamment dans le cas d'association avec des substances facilitant le bon état du cuir chevelu et du cheveu. On peut citer les associations avec des mucopolysaccharides, des minéraux, des vitamines, des céramides, des huiles végétales, des substances antiradicalaires, des filtres U.V., des acides de fleurs ou de fruits.  The derivatives of formula (I) capable of inhibiting chemokines may, in the compositions used, be associated with one another or with other compounds that complement or indeed synergize this effect. The protective activity of the derivatives of formula (I) with respect to free radicals and UV is interesting in the hair field, especially in the case of combination with substances facilitating the good condition of the scalp and hair . It is possible to mention associations with mucopolysaccharides, minerals, vitamins, ceramides, vegetable oils, antiradical substances, U.V. filters, flower acids or fruit acids.
De même, l'activité réparatrice des composés de formule (I) capable d'inhiber les chimiokines est particulièrement intéressante, quand ils sont associés avec des substances ayant un effet cicatrisant comme des protéines, l'acide hyaluronique , des acides aminés, ou avec des substances anti-inflammatoires, anti-âge, après-solaire anti-acné ou anti-dermatose.  Similarly, the restorative activity of compounds of formula (I) capable of inhibiting chemokines is particularly advantageous when they are associated with substances having a healing effect such as proteins, hyaluronic acid, amino acids, or with anti-inflammatory substances, anti-aging, after-sun anti-acne or anti-dermatosis.
Ainsi, les compositions mises en œuvre selon l'invention sont tout particulièrement adaptées à une application topique pour prévenir et/ou traiter de nombreuses altérations cutanées, notamment comme agent réparateur et/ou protecteur de la peau et du système pileux comme les cheveux, pour lutter contre les agressions externes liées à la pollution, au soleil, au stress oxydatif, au vieillissement et aux pathologies cutanées entraînant un dysfonctionnement de 1 ' homéostasie de l'épiderme ou des cheveux. Ces compositions cosmétiques mises en œuvre selon l'invention peuvent aussi prendre la forme de lotions ou solutions dans lesquelles les composés de formule (I) sont sous forme encapsulée, par exemple dans des microsphères. Ces microsphères peuvent, par exemple, être constituées de corps gras, d'agar et d'eau. Les agents actifs peuvent être aussi incorporés dans des vecteurs de type liposomes, glycosphères, dans des chylomicrons, des macro-, micro-, nanoparticules ainsi que les macro-, micro- et nanocapsules et aussi être adsorbés sur des polymères organiques poudreux, les talcs, bentonites et autres supports minéraux. Thus, the compositions used according to the invention are particularly suitable for topical application for preventing and / or treating numerous skin disorders, especially as a repairing and / or protective agent for the skin and the hair system, such as the hair, for to fight against external aggressions related to pollution, sun, oxidative stress, aging and skin pathologies leading to dysfunction of homeostasis of the epidermis or hair. These cosmetic compositions implemented according to the invention may also take the form of lotions or solutions in which the compounds of formula (I) are in encapsulated form, for example in microspheres. These microspheres may, for example, consist of fat, agar and water. The active agents may also be incorporated into liposome, glycosphere-type vectors in chylomicrons, macro-, micro-, nanoparticles as well as macro-, micro- and nanocapsules and also be adsorbed onto powdery organic polymers, talcs , bentonites and other mineral supports.
Pour la préparation des compositions mises en œuvre selon l'invention, les composés de formule (I) peuvent être mélangés aux excipients généralement employés en cosmétique. Les compositions cosmétiques mises en œuvre selon l'invention peuvent donc contenir des additifs ou des adjuvants usuels en cosmétologie, comme par exemple des agents antibactériens ou des parfums mais aussi des lipides d'extraction et/ou de synthèse, des polymères gélifiants et viscosants, des tensio-actifs, des émulsifiants , des actifs hydro- ou lipo-solubles , des extraits de plantes, des extraits tissulaires, des extraits marins, ou des actifs de synthèse .  For the preparation of the compositions used according to the invention, the compounds of formula (I) may be mixed with the excipients generally used in cosmetics. The cosmetic compositions used according to the invention may therefore contain additives or adjuvants customary in cosmetology, such as, for example, antibacterial agents or perfumes, but also extraction and / or synthetic lipids, gelling and viscosity polymers, surfactants, emulsifiers, hydro- or liposoluble active agents, plant extracts, tissue extracts, marine extracts, or synthetic actives.
L'utilisation dermo-cosmétique ou pharmaceutique des composés de formule (I) comprend tous les produits de soin du corps et de la peau, y compris les produits solaires, protecteurs et bronzants, les produits anti-âge, anti-séborrhéiques, toniques, les produits assurant l'amélioration de l'aspect de la peau y compris le traitement acnéique, le traitement des rougeurs cutanées, le traitement du cuir chevelu et celui de la chute des cheveux.  The dermo-cosmetic or pharmaceutical use of the compounds of formula (I) includes all skincare and skin care products, including sun, protective and tanning products, anti-aging, anti-seborrhoeic, tonic products, products that improve the appearance of the skin, including acne treatment, skin rash treatment, scalp treatment and hair loss.
Les compositions cosmétiques mises en œuvre selon la présente invention peuvent aussi comprendre d'autres agents actifs complémentaires choisis pour leur action, par exemple pour la protection solaire, l'effet anti-rides, l'activité antiradicalaire et antioxydante, l'activité anti-irritante, la nutrition cellulaire, la respiration cellulaire, l'hydratation et la régénération cellulaire, les traitements anti-séborrhéïques , ainsi que d'autres agents actifs ayant une action sur la tonicité cutanée et la protection du cheveu. The cosmetic compositions used according to the present invention may also comprise other agents complementary active ingredients chosen for their action, for example for sunscreen, anti-wrinkle effect, antiradical and antioxidant activity, anti-irritant activity, cellular nutrition, cellular respiration, hydration and cellular regeneration , anti-seborrhoeic treatments, as well as other active agents having an action on the skin tonicity and the protection of the hair.
Les compositions cosmétiques mises en œuvre selon la présente invention sont, de préférence, à utiliser quotidiennement en les appliquant une ou plusieurs fois par jour.  The cosmetic compositions used according to the present invention are, preferably, to be used daily by applying them one or more times per day.
Les compositions cosmétiques mises en œuvre selon la présente invention sont très bien tolérées, elles ne · présentent aucune phototoxicité et leur application sur la peau, pour des périodes de temps prolongées, n'implique aucun effet systémique.  The cosmetic compositions used according to the present invention are very well tolerated, they have no phototoxicity and their application to the skin for prolonged periods of time does not imply any systemic effect.
L'invention concerne aussi l'utilisation de composés de formule (I) pour la préparation de compositions pharmaceutiques présentant une activité anti-inflammatoire et/ou dermoprotectrice . Ces compositions sont utiles pour prévenir et/ou traiter notamment des maladies dermatologiques liées à des activités séborrhéiques, acnéiques, inflammatoires et immunologiques.  The invention also relates to the use of compounds of formula (I) for the preparation of pharmaceutical compositions having an anti-inflammatory and / or dermoprotective activity. These compositions are useful for preventing and / or treating in particular dermatological diseases related to seborrheic, acneic, inflammatory and immunological activities.
En résumé, l'invention se rapporte donc à l'utilisation d'une composition pharmaceutique, dermatologique ou cosmétique, contenant des composés de . formule (I) capables d'inhiber certaines chimiokines, destinées à prévenir et/ou traiter les pathologies et désordres résultant :  In summary, the invention thus relates to the use of a pharmaceutical, dermatological or cosmetic composition containing compounds of. formula (I) capable of inhibiting certain chemokines, intended to prevent and / or treat pathologies and disorders resulting from:
du vieillissement naturel ou prématuré de la peau ou des cheveux ; de dermatoses, comme le psoriasis, l'acné et la dermatite atopique ; natural or premature aging of the skin or hair; dermatoses, such as psoriasis, acne and atopic dermatitis;
d'états inflammatoires et/ou immunitaires des systèmes cutanés ou pileux, induisant des démangeaisons, irritations, rougeurs chroniques, irritations et démangeaisons persistantes, et des troubles fonctionnels de la fragilité capillaire. inflammatory and / or immune conditions of the cutaneous or hair systems, inducing itching, irritation, chronic redness, irritation and persistent itching, and functional disorders of capillary fragility.
La présente invention est maintenant illustrée par les exemples donnés ci-après.  The present invention is now illustrated by the examples given below.
Les exemples 1 à 3 illustrent un procédé de préparation de composés de formule (I) capable d'inhiber la chimiokine CCL22 selon l'invention.  Examples 1 to 3 illustrate a process for the preparation of compounds of formula (I) capable of inhibiting the CCL22 chemokine according to the invention.
Les produits de départ sont disponibles dans le commerce ou peuvent être synthétisés par des méthodes classiques connues de l'homme du métier.  The starting materials are commercially available or can be synthesized by conventional methods known to those skilled in the art.
Exemple 1 : Example 1
Synthèse du 2 , 3-dihydroxypropyl 2-hydroxybenzoate (codé GPN136) Synthesis of 2,3-dihydroxypropyl 2-hydroxybenzoate (GPN136 coded)
1 GPN000136 Dans un ballon sous argon, 2.17 g (3.15 éq. ) de 1H- benzotriazole sont dissous dans 30 mL de tétrahydrofurane anhydre, puis 0.42 mL (1 éq.) de chlorure de thionyle sont ajoutés. Le mélange est agité pendant 45 minutes à température ambiante puis 800 mg (5.792 mmol ; 1 éq. ) d'acide salicylique dissous dans 20 mL de tétrahydrofurane anhydre sont additionnés. Le milieu réactionnel est agité 3 heures à température ambiante. Il est ensuite filtré rapidement sur fritté. Le filtrat est évaporé pour conduire à l'acide activé (benzotriazol-l-yl (2-hydroxyphényl) métha- none) qui est directement engagé dans l'étape suivante. Dans un ballon sous argon, 696 mg (5.266 mmol) de solkétal sont dissous dans 10 mL de tétrahydrofurane anhydre et 232 mg (1.1 éq.) d'hydrure de sodium (60% dans l'huile) sont ajoutés. Le mélange est agité 30 minutes à température ambiante. Puis 1.1 éq. (5.792 mmol) de benzotriazol-l-yl (2- hydroxyphényl ) méthanone en solution dans 20 mL de tétrahydrofurane anhydre sont ajoutés. Le milieu réactionnel est agité 5 heures à température ambiante, puis hydrolysé avec 30 mL d'eau. Il est extrait au dichlorométhane (3 fois 30 mL) . Les phases organiques rassemblées sont séchées sur sulfate de magnésium, filtrées et évaporées sous pression réduite. Le brut est purifié par chromatographie sur gel de silice (éther de pétrole / acétate d'éthyle 9/1) pour conduire à 1.16 g (rendement : 87%) de produit attendu codé 1 sous forme d'une huile incolore. 1 GPN000136 In a flask under argon, 2.17 g (3.15 eq) of 1H-benzotriazole are dissolved in 30 mL of anhydrous tetrahydrofuran and then 0.42 mL (1 eq) of thionyl chloride are added. The mixture is stirred for 45 minutes at room temperature and then 800 mg (5.792 mmol, 1 eq) of salicylic acid dissolved in 20 mL of anhydrous tetrahydrofuran are added. The reaction medium is stirred for 3 hours at room temperature. It is then filtered quickly on sintered. The filtrate is evaporated to yield the activated acid (benzotriazol-1-yl (2-hydroxyphenyl) methanone) which is directly engaged in the next step. In a flask under argon, 696 mg (5.266 mmol) of solketal are dissolved in 10 mL of anhydrous tetrahydrofuran and 232 mg (1.1 eq) of sodium hydride (60% in oil) are added. The mixture is stirred for 30 minutes at room temperature. Then 1.1 eq. (5.792 mmol) of benzotriazol-1-yl (2-hydroxyphenyl) methanone dissolved in 20 mL of anhydrous tetrahydrofuran are added. The reaction medium is stirred for 5 hours at room temperature and then hydrolysed with 30 ml of water. It is extracted with dichloromethane (3 times 30 mL). The combined organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude is purified by chromatography on silica gel (petroleum ether / ethyl acetate 9/1) to give 1.16 g (yield: 87%) of the expected product coded 1 in the form of a colorless oil.
RMN XH (250 MHz, CDC13) : δ 1,39 (s, 3H, CH3) ; 1.46 (s, 3H, CH3) ; 3.89 (dd, 1H, J = 5.3 et 8.7 Hz, CH2) ; 4.16 (dd, 1H, J = 6.2 et 8.7 Hz, CH2) ; 4.33 - 4.51 (m, 3H, CH2 et CH) ; 6.89 (td, 1H, J = 1.2 et 8.0 Hz, CH Ar) ; 6.99 (dd, 1H, J = 0.9 et 8.3 Hz, CH Ar) ; 7.47 (td, 1H, J = 1.6 et 8.3 Hz, CH ■Ar) ; 7.87 (dd, 1H, J = 1.6 et 8.0 Hz, CH Ar) ; 10.62 (s, 1H, OH) . X NMR H (250 MHz, CDC1 3): δ 1.39 (s, 3H, CH 3); 1.46 (s, 3H, CH 3 ); 3.89 (dd, 1H, J = 5.3 and 8.7 Hz, CH 2 ); 4.16 (dd, 1H, J = 6.2 and 8.7 Hz, CH 2 ); 4.33 - 4.51 (m, 3H, CH 2 and CH); 6.89 (td, 1H, J = 1.2 and 8.0 Hz, CH Ar); 6.99 (dd, 1H, J = 0.9 and 8.3 Hz, CH Ar); 7.47 (td, 1H, J = 1.6 and 8.3 Hz, CH ■ Ar); 7.87 (dd, 1H, J = 1.6 and 8.0 Hz, CH Ar); 10.62 (s, 1H, OH).
Dans un ballon, 1 g (3.9640 mmol) du composé codé 1 sont dissous dans 25 mL de méthanol et 1.2 g de résine Amberlyst 15 activée sont ajoutés. Le milieu est agité pendant 19 heures à température ambiante, filtré sur fritté. La résine est rincée avec du méthanol. Le filtrat est ensuite évaporé sous pression réduite. Le brut est purifié par chromatographie sur gel de silice (éther de pétrole / acétate d'éthyle : 5/5 puis 3/7) pour conduire à 620 mg du composé codé GPN000136 (rendement : 74%) sous forme d'un solide blanc. RMN 2H (250 MHz, CDC13) .61 (si, 1H, OH) ; 3.07 (si,In a flask, 1 g (3.9640 mmol) of coded Compound 1 is dissolved in 25 mL of methanol and 1.2 g of activated Amberlyst 15 resin are added. The medium is stirred for 19 hours at room temperature, filtered on sintered. The resin is rinsed with methanol. The filtrate is then evaporated under reduced pressure. The crude product is purified by chromatography on silica gel (petroleum ether / ethyl acetate: 5/5 then 3/7) to give 620 mg of the coded compound GPN000136 (yield: 74%) in the form of a white solid. . 2 H NMR (250 MHz, CDCl 3 ) .61 (si, 1H, OH); 3.07 (if,
1H, OH) ; 3.68 - 3.78 (m, 2H, CH2) ; 4.05 - 4.15 (m, 1H, CH) ; 4.39 - 4.51 (m, 2H, CH2) ; 6.88 (td, 1H, J = 1.0 et1H, OH); 3.68 - 3.78 (m, 2H, CH 2 ); 4.05 - 4.15 (m, 1H, CH); 4.39 - 4.51 (m, 2H, CH 2 ); 6.88 (td, 1H, J = 1.0 and
7.6 Hz, CH Ar) ; 6.98 (dd, 1H, J = 0.9 et 8.4 Hz, CH Ar) ; 7.46 (td, 1H, J = 1.7 et 7.7 Hz, CH Ar) ; 7.84 (dd, 1H, J =7.6 Hz, CH Ar); 6.98 (dd, 1H, J = 0.9 and 8.4 Hz, CH Ar); 7.46 (td, 1H, J = 1.7 and 7.7 Hz, CH Ar); 7.84 (dd, 1H, J =
1.7 et 8.0 Hz, CH Ar) ; 10.57 (s, 1H, OH). 1.7 and 8.0 Hz, CH Ar); 10.57 (s, 1H, OH).
RMN 13C (62.5 MHz, CDC13) : 63.5 (CH2) ; 65.6 (CH2) ; 70.2 (CH) ; 112.1 (Cq) ; 117.9 (CH) ; 119.4 (CH) ; 130.0 (CH) ; 136.2 (CH) ; 161.8 (Cq) ; 170.3 (Cq) . 13 C NMR (62.5 MHz, CDCl 3 ): 63.5 (CH 2 ); 65.6 (CH 2 ); 70.2 (CH); 112.1 (Cq); 117.9 (CH); 119.4 (CH); 130.0 (CH); 136.2 (CH); 161.8 (Cq); 170.3 (Cq).
Exemple 2 : Synthèse du -dihydroxypropyl 2- hydroxybenzoate (codé GPS008506) Example 2 Synthesis of Dihydroxypropyl-Hydroxybenzoate (Coded GPS008506)
Dans un ballon sous argon, 0.3 mL (2.4194 mmol) de (R) - 2,3- O-isopropylidéne glycérol sont dissous dans 5 mL de tétrahydrofurane anhydre et 106 mg (1.1 éq.) d'hydrure de sodium (60% dans l'huile) sont ajoutés. Le mélange est agité pendant 30 minutes à température ambiante. Puis 637 mg (1.1 éq.) d'acide activé décrit précédemment (benzotriazol-1- yl (2-hydroxyphenyl) methanone) dissous dans 12 mL de tétrahydrofurane anhydre sont additionnés. Le milieu réactionnel est agité 4 heures à température ambiante puis hydrolysé avec 40 mL d'eau. Il est extrait au dichlorométhane (3 fois 30 mL) . Les phases organiques rassemblées sont séchées sur sulfate de magnésium, filtrées et évaporées sous pression réduite. Le brut est purifié par chromatographie sur gel de silice (éther de pétrole / acétate d' éthyle 9/1) pour conduire à 520 mg (rendement : 85%) du produit attendu (codé 2) sous forme d'une huile incolore . In a flask under argon, 0.3 mL (2.4194 mmol) of (R) -2,3-O-isopropylidene glycerol are dissolved in 5 mL of anhydrous tetrahydrofuran and 106 mg (1.1 eq) of sodium hydride (60% in oil) are added. The mixture is stirred for 30 minutes at room temperature. Then 637 mg (1.1 eq) of previously described activated acid (benzotriazol-1-yl (2-hydroxyphenyl) methanone) dissolved in 12 mL of anhydrous tetrahydrofuran are added. The reaction medium is stirred for 4 hours at room temperature and then hydrolyzed with 40 ml of water. It is extracted with dichloromethane (3 times 30 mL). The combined organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude is purified by chromatography on silica gel (petroleum ether / ethyl acetate 9/1) to yield 520 mg (yield: 85%) of the expected product (coded 2) as a colorless oil.
RMN 1ti (250 MHz, CDC13) : δ 1,39 (s, 3H, CH3) ; 1.46 (s, 3H, CH3) ; 3.89 (dd, 1H, J = 5.3 et 8.7 Hz, CH2) ; 4.16 (dd, 1H, J = 6.2 et 8.7 Hz, CH2) ; 4.33 - 4.51 (m, 3H, CH2 et CH) ; 6.89 (td, 1H, J = 1.2 et 8.0 Hz, CH Ar) ; 6.99 (dd, 1H, J = 0.9 et 8.3 Hz, CH Ar) ; 7.47 (td, 1H, J = 1.6 et 8.3 Hz, CH Ar) ; 7.87 (dd, 1H, J = 1.6 et 8.0 Hz, CH Ar) ; 10.62 (s, 1H, OH) . 1 H NMR (250 MHz, CDCl 3 ): δ 1.39 (s, 3H, CH 3 ); 1.46 (s, 3H, CH 3 ); 3.89 (dd, 1H, J = 5.3 and 8.7 Hz, CH 2 ); 4.16 (dd, 1H, J = 6.2 and 8.7 Hz, CH 2 ); 4.33 - 4.51 (m, 3H, CH 2 and CH); 6.89 (td, 1H, J = 1.2 and 8.0 Hz, CH Ar); 6.99 (dd, 1H, J = 0.9 and 8.3 Hz, CH Ar); 7.47 (td, 1H, J = 1.6 and 8.3 Hz, CH Ar); 7.87 (dd, 1H, J = 1.6 and 8.0 Hz, CH Ar); 10.62 (s, 1H, OH).
Dans un ballon, 650 mg (2-.5766 mmol) du composé codé 2 sont dissouts dans 10 mL de méthanol et 800 mg de résine Amberlyst 15 activée sont ajoutés. Le milieu est agité 24 heures à température ambiante, filtré sur fritté. La résine est rincée avec du méthanol. Le filtrat est ensuite évaporé sous pression réduite. Le brut est purifié par chromatographie sur gel de silice (éther de pétrole / acétate d'éthyle : 6/4, 4/6 puis 3/7) pour conduire à 440 mg du composé référencé GPS008506 (rendement : 80%) sous forme d'un solide blanc. Pouvoir rotatoire : aD = +15.5 (c = 1 ; EtOH) . In a flask, 650 mg (2-.5766 mmol) of coded compound 2 are dissolved in 10 mL of methanol and 800 mg of activated Amberlyst 15 resin are added. The medium is stirred for 24 hours at room temperature, filtered on sintered. The resin is rinsed with methanol. The filtrate is then evaporated under reduced pressure. The crude is purified by chromatography on silica gel (petroleum ether / ethyl acetate: 6/4, 4/6 and then 3/7) to give 440 mg of the compound referenced GPS008506 (yield: 80%) in the form of a white solid. Rotatory power: at D = +15.5 (c = 1, EtOH).
RMN XH (250 MHz, CDC13) : δ 2.61 (si, 1H, OH) ; 3.07 (si, 1H, OH) ; 3.68 - 3.78 (m, 2H, CH2) ; 4.05 - 4.15 (m, 1H, CH) ; 4.39 - 4.51 (m, 2H, CH2) ; 6.88 (td, 1H, J = 1.0 et X NMR H (250 MHz, CDC1 3): δ 2.61 (bs, 1H, OH); 3.07 (si, 1H, OH); 3.68 - 3.78 (m, 2H, CH 2 ); 4.05 - 4.15 (m, 1H, CH); 4.39 - 4.51 (m, 2H, CH 2 ); 6.88 (td, 1H, J = 1.0 and
7.6 Hz, CH Ar) ; 6.98 (dd, 1H, J = 0.9 et 8.4 Hz, CH Ar) ; 7.46 (td, 1H, J = 1.7 et 7.7 Hz, CH Ar) ; 7.84 (dd, 1H, J =7.6 Hz, CH Ar); 6.98 (dd, 1H, J = 0.9 and 8.4 Hz, CH Ar); 7.46 (td, 1H, J = 1.7 and 7.7 Hz, CH Ar); 7.84 (dd, 1H, J =
1.7 et 8.0 Hz, CH Ar) ; 10.57 (s, 1H, OH). 1.7 and 8.0 Hz, CH Ar); 10.57 (s, 1H, OH).
RMN 13C (62.5 MHz, CDC13) : δ 63.5 (CH2) ; 65.6 (CH2) ; 70.2 (CH) ; 112.1 (Cq) ; 117.9 (CH) ; 119.4 (CH) ; 130.0 (CH) ; 136.2 (CH) ; 161.8 (Cq) ; 170.3 (Cq) . 13 C NMR (62.5 MHz, CDCl 3 ): δ 63.5 (CH 2 ); 65.6 (CH 2 ); 70.2 (CH); 112.1 (Cq); 117.9 (CH); 119.4 (CH); 130.0 (CH); 136.2 (CH); 161.8 (Cq); 170.3 (Cq).
Exemple 3 : Synthèse du (R) -2 , 3-dihydroxypropyl 2-hydroxybenzoate (codé GPS008505) Example 3 Synthesis of (R) -2,3-dihydroxypropyl 2-hydroxybenzoate (coded GPS008505)
Dans un ballon sous argon, 0.4 mL (3.2385 mmol) de (S)- 2,3- O-isopropylidene glycérol sont dissous dans 7 mL de tétrahydrofurane anhydre et 142 mg (1.1 éq.) d'hydrure de sodium (60% dans l'huile) sont ajoutés. Le mélange est agité 30 minutes à température ambiante. Puis 852 mg (1.1 éq.) d'acide activé décrit précédemment (benzotriazol-l-yl (2- hydroxyphenyl ) methanone) dissous dans 16 mL de tétrahydrofurane anhydre sont additionnés. Le milieu réactionnel est agité 5 heures à température ambiante puis hydrolysé avec 40 mL d'eau. Il est extrait au dichlorométhane (3 fois 30 mL) . Les phases organiques rassemblées sont séchées sur sulfate de magnésium, filtrées et évaporées sous pression réduite. Le brut est purifié par chromatographie sur gel de silice (éther de pétrole ./ acétate d' éthyle 9/1) pour conduire à 730 mg (rendement : 89%) du produit attendu (codé 3) sous forme d'une huile incolore. In a flask under argon, 0.4 mL (3.2385 mmol) of (S) -2,3-O-isopropylidene glycerol are dissolved in 7 mL of anhydrous tetrahydrofuran and 142 mg (1.1 eq) of sodium hydride (60% in oil) are added. The mixture is stirred for 30 minutes at room temperature. Then 852 mg (1.1 eq) of previously described activated acid (benzotriazol-1-yl (2-hydroxyphenyl) methanone) dissolved in 16 mL of anhydrous tetrahydrofuran are added. The reaction medium is stirred for 5 hours at room temperature and then hydrolyzed with 40 ml of water. It is extracted with dichloromethane (3 times 30 mL). The combined organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude is purified by chromatography on silica gel (petroleum ether / ethyl acetate to 9/1 ethyl.) To afford 730 mg (yield: 89%) of the expected product (coded 3) as a colorless oil.
RMN XH (250 MHz, CDC13) : δ 1,39 (s, 3H, CH3) ; 1.46 (s, 3H, CH3) ; 3.89 (dd, 1H, J = 5.3 et 8.7 Hz, CH2) ; 4.16 (dd, 1H, J = 6.2 et 8.7 Hz, CH2) ; 4.33 - 4.51 (m, 3H, CH2 et CH) ; 6.89 (td, 1H, J = 1.2 et 8.0 Hz, CH Ar) ; 6.99 (dd, 1H, J = 0.9 et 8.3 Hz, CH Ar) ; 7.47 (td, 1H, J = 1.6 et 8.3 Hz, CH Ar) ; 7.87 (dd, 1H, J = 1.6 et 8.0 Hz, CH Ar) ; 10.62 (s, 1H, OH) . X NMR H (250 MHz, CDC1 3): δ 1.39 (s, 3H, CH 3); 1.46 (s, 3H, CH 3 ); 3.89 (dd, 1H, J = 5.3 and 8.7 Hz, CH 2 ); 4.16 (dd, 1H, J = 6.2 and 8.7 Hz, CH 2 ); 4.33 - 4.51 (m, 3H, CH 2 and CH); 6.89 (td, 1H, J = 1.2 and 8.0 Hz, CH Ar); 6.99 (dd, 1H, J = 0.9 and 8.3 Hz, CH Ar); 7.47 (td, 1H, J = 1.6 and 8.3 Hz, CH Ar); 7.87 (dd, 1H, J = 1.6 and 8.0 Hz, CH Ar); 10.62 (s, 1H, OH).
Dans un ballon, 650 mg (2.5766 mmol). du composé codé 3 sont dissous dans 15 mL de méthanol et 800 mg de résine Amberlyst 15 activée sont ajoutés. Le milieu est agité 24 heures à température ambiante, filtré sur fritté. La résine est rincée avec du méthanol. Le filtrat est ensuite évaporé sous pression réduite. Le brut est purifié par chromatographie sur gel de silice (éther de pétrole / acétate d'éthyle : 5/5 puis 3/7) pour conduire à 480 mg du composé référencé GPS008505 (rendement : 87%) sous forme d'un solide blanc. Pouvoir rotatoire : D = -16.6 (c = 1 ; EtOH) . In a flask, 650 mg (2.5766 mmol). of coded compound 3 are dissolved in 15 mL of methanol and 800 mg of activated Amberlyst 15 resin are added. The medium is agitated 24 hours to room temperature, filtered on sintered. The resin is rinsed with methanol. The filtrate is then evaporated under reduced pressure. The crude product is purified by chromatography on silica gel (petroleum ether / ethyl acetate: 5/5 then 3/7) to give 480 mg of the compound referenced GPS008505 (yield: 87%) in the form of a white solid. . Rotatory power: D = -16.6 (c = 1, EtOH).
R N 1 (250 MHz, CDC13) : δ 2.61 (si, 1H, OH) ; 3.07 (si, 1H, OH) ; 3.68 - 3.78 (m, 2H, CH2) ; 4.05 - 4.15 (m, 1H, CH) ; 4.39 - 4.51 (m, 2H, CH2) ; 6.88 (td, 1H, J = 1.0 etRN 1 (250 MHz, CDCl 3 ): δ 2.61 (si, 1H, OH); 3.07 (si, 1H, OH); 3.68 - 3.78 (m, 2H, CH 2 ); 4.05 - 4.15 (m, 1H, CH); 4.39 - 4.51 (m, 2H, CH 2 ); 6.88 (td, 1H, J = 1.0 and
7.6 Hz, CH Ar) ; 6.98 (dd, 1H, J = 0.9 et 8.4 Hz, CH Ar) ; 7.46 (td, 1H, J = 1.7 et 7.7 Hz, CH Ar) ; 7.84 (dd, 1H, J =7.6 Hz, CH Ar); 6.98 (dd, 1H, J = 0.9 and 8.4 Hz, CH Ar); 7.46 (td, 1H, J = 1.7 and 7.7 Hz, CH Ar); 7.84 (dd, 1H, J =
1.7 et 8.0 Hz, CH Ar) ; 10.57 (s, 1H, OH). 1.7 and 8.0 Hz, CH Ar); 10.57 (s, 1H, OH).
RMN 13C (62.5 MHz, CDC13) : δ 63.5 (CH2) ; 65.6 (CH2) ; 70.2 (CH) ; 112.1 (Cq) ; 117.9 (CH) ; 119.4 (CH) ; 130.0 (CH) ; 136.2 (CH) ; 161.8 (Cq) ; 170.3 (Cq) . 13 C NMR (62.5 MHz, CDCl 3 ): δ 63.5 (CH 2 ); 65.6 (CH 2 ); 70.2 (CH); 112.1 (Cq); 117.9 (CH); 119.4 (CH); 130.0 (CH); 136.2 (CH); 161.8 (Cq); 170.3 (Cq).
L' exemple 4 met en évidence le protocole technique permettant d'enregistrer les effets des produits selon l'invention sur les chimiokines.  Example 4 demonstrates the technical protocol for recording the effects of the products according to the invention on the chemokines.
Exemple 4 : Example 4
Propriétés inhibitrices des dérivés de formule (I) sur les chimiokines .  Inhibitory properties of the derivatives of formula (I) on chemokines.
Cellules exprimant le récepteur CCR4 des chimiokines  Cells expressing the CCR4 receptor of chemokines
Afin de permettre un enregistrement aisé des réponses associées au récepteur CCR4, le cDNA qui permet son expression est cloné dans le plasmide pIRES (ClonTech) en fusion avec la protéine GFP, selon Vollmer et al. (1999), ce qui permet de mesurer aisément l'expression du récepteur chimérique EGFP-CCR . Les cellules HEK 293 (ATCC) sont cultivées dans le milieu minimum essentiel MEM (Invitrogen) en présence de 10% de sérum de veau fœtal (Gibco-BRL) , 100 U/mL pénicilline (Invitrogen), 100 ag/mL streptomycine (Invitrogen) et 2 mM L-glutamine (Invitrogen) à 37°C dans atmosphère saturée en eau et contenant 5% C02. Les cellules sont transfectées selon la méthode du précipité de phosphate de calcium de Chen et Okayama, 1986, et les cellules ayant incorporé le plasmide d'expression sont sélectionnées à l'aide de 600 ag/mL de geneticine G-418 (PAA) pendant 5 semaines. Les clones sont sélectionnés après avoir été caractérisés par microscopie de fluorescence et analyse cytometrique au FACS ( fluorescence-assisted cell sorting) . Construction de la protéine recombinante Gqi5 In order to allow easy recording of the CCR4 receptor-associated responses, the cDNA that allows its expression is cloned into the plasmid pIRES (ClonTech) in fusion with the GFP protein, according to Vollmer et al. (1999), which makes it easy to measure the expression of the EGFP-CCR chimeric receptor. The HEK 293 (ATCC) cells are cultured in MEM minimum essential medium (Invitrogen) in the presence of 10% fetal calf serum (Gibco-BRL), 100 U / mL penicillin (Invitrogen), 100 μg / mL streptomycin (Invitrogen) ) and 2 mM L-glutamine (Invitrogen) at 37 ° C in atmosphere saturated with water and containing 5% CO2. The cells are transfected according to the calcium phosphate precipitate method of Chen and Okayama, 1986, and the cells having incorporated the expression plasmid are selected using 600 μg / ml of geneticin G-418 (PAA) for 5 weeks. The clones are selected after having been characterized by fluorescence microscopy and fluorescence-assisted cell sorting (FACS) cytometric analysis. Construction of the recombinant protein Gqi5
Afin de permettre un enregistrement aisé des réponses cellulaires associées au récepteur CCR4, on modifie son couplage naturel à' l'inhibition de production d'AMPc vers un couplage à la phospholipase C qui permet des mesures de calcium. On produit dans ce but la protéine chimérique Gqi5 par mutagénèse dirigée des 5 derniers acides aminés de Gq que l'on remplace par leurs homologues de Gi. Les cellules exprimant le récepteur CCR4 sont transfectées par le plasmide pCNA3.1 dans lequel le cDNA codant Gqi5 a été incorporé. Les enregistrements de réponses calciques sont réalisés le lendemain de la transfection . In order to permit easy registration of cellular responses associated with CCR4 receptor, its natural coupling is changed to 'inhibition of cAMP production to coupling to phospholipase C, which allows calcium measurements. For this purpose, the chimeric protein Gq15 is produced by site-directed mutagenesis of the last 5 amino acids of Gq, which are replaced by their Gi counterparts. The cells expressing the CCR4 receptor are transfected with the plasmid pCNA3.1 in which the cDNA encoding Gq15 was incorporated. Recordings of calcium responses are made the day after transfection.
Enregistrement des réponses calciques cellulaires et de leur inhibition par les molécules de la collection GPN :  Recording cellular calcium responses and their inhibition by the GPN collection molecules:
Les cellules sont chargées en indicateur fluorescent du calcium, INDO-1, selon le protocole fourni par le fournisseur (Molecular probes), distribuées dans des puits de microplaques et placées dans un lecteur-pipetteur de fluorescence ( FlexStation, Molecular devices) . L'élévation de calcium intracellulaire est mesurée par changement d'intensité de fluorescence à 401 et 475 nm (excitation 355 nm) . Des points de mesures sont enregistrés chaques 5s pendant 150s pour chaque puits. Les molécules sont testées en présence de 5 nM de chimiokine CCL22 (commerciale) La figure 1 illustre de manière générale les résultats obtenus : l'addition de chimiokine (CK) à des cellules exprimant le récepteur de chimiokine (C R) déclenche une libération de calcium intracellulaire recelée par le changement de fluorescence de la sonde calcique Indo-1. La réponse se développe en quelques secondes et s'atténue avec le temps pour atteindre le retour en 2 minutes environ pour une concentration de 5 à 10 nM de la chimiokine CCL22 sur des cellules HEK 293 exprimant CCR4. Si l'on préincube les molécules à tester avec la chimiokine [CK+N] et qu'on ajoute le mélange aux cellules, on observe une forte diminution de l'amplitude de la réponse si la molécule à tester est un neutraligand de la chimiokine. Inversement lorsqu'on préincube le neutraligand avec les cellules exprimant le récepteur [CKR + N] on observe une bien moindre diminution de l'amplitude de la réponse. The cells are loaded with the INDO-1 fluorescent calcium indicator, according to the protocol provided by the supplier (Molecular probes), distributed in microplate wells and placed in a fluorescence reader-pipettor (FlexStation, Molecular devices). The elevation of intracellular calcium is measured by changing fluorescence intensity at 401 and 475 nm (excitation 355 nm). Measuring points are recorded every 5s for 150s for each well. The molecules are tested in the presence of 5 nM chemokine CCL22 (commercial) FIG. 1 generally illustrates the results obtained: the addition of chemokine (CK) to cells expressing the chemokine receptor (CR) triggers an intracellular calcium release that is harnessed by the fluorescence change of the Indo-1 calcium probe. The response develops in a few seconds and diminishes with time to reach the return in about 2 minutes for a concentration of 5 to 10 nM of the chemokine CCL22 on HEK 293 cells expressing CCR4. If the test molecules are preincubated with the chemokine [CK + N] and the mixture is added to the cells, a marked decrease in the amplitude of the response is observed if the test molecule is a chemokine neutraligand. . Conversely, when the neutraligand is preincubated with the cells expressing the [CKR + N] receptor, a much smaller decrease in the amplitude of the response is observed.
Ce protocole a été employé pour identifier les neutraligands de CCL22 présentés dans le tableau 1.  This protocol was used to identify the CCL22 neutraligands shown in Table 1.
L' affinité apparente des molécules de GPN136 est déterminée par l'établissement d'une relation dose-effet de l'inhibition de la réponse calcique ainsi que présenté en figure 2 et les résultats obtenus sont reportés dans le tableau 1.  The apparent affinity of the GPN136 molecules is determined by the establishment of a dose-response relationship of the inhibition of the calcium response as presented in FIG. 2 and the results obtained are reported in Table 1.
relations structure/fonction des dérivés structure / function relationships of derivatives
TABLEAU 1 TABLE 1
L'analyse de la sélectivité des molécules est réalisée par mesure d'inhibition de la réponse évoquée par d'autres chimiokines sur leurs récepteurs respectifs ainsi, dans la figure 3, les molécules ont été testée sur les paires CCL2/CCR2, CCL3-5/CCR5, CCL17/CCR4, CCL22/CCR4, CXCL8/CXCR8, CXCL10/CXCR2, CXCL11/CXCR3 , CXCL12/CXCR4 La figure 3 donne la sélectivité des neutraligands de CCL22 (GPN136 (barres noires) et GPN025 (barres blanches) ) sur les chimiokines indiquées et leurs récepteurs respectifs. The analysis of the selectivity of the molecules is carried out by measurement of inhibition of the evoked response by other chemokines on their respective receptors and, in FIG. 3, the molecules have been tested on the CCL2 / CCR2, CCL3-5 pairs. / CCR5, CCL17 / CCR4, CCL22 / CCR4, CXCL8 / CXCR8, CXCL10 / CXCR2, CXCL11 / CXCR3, CXCL12 / CXCR4 Figure 3 shows the selectivity of CCL22 neutralizers (GPN136 (black bars) and GPN025 (white bars)) on the indicated chemokines and their respective receptors.
Détermination de l'affinité d'interaction des neutraligands de CCL22 par extinction de fluorescence des résidus de tryptophane . Determination of the interaction affinity of CCL22 neutraligands by quenching fluorescence of tryptophan residues.
Cette mesure est réalisée comme décrit dans Hachet-Haas et al. (Small neutralizing molécules to inhibit actions of the chemokine CXCL12 , J Biol Chem, 2008, 283(34), 23189-99). Brièvement : les mesures de fluorescence sont réalisées sur un spectrofluorimètre Fluorolog 3 ( JobinYvon/Spex) dans une cuvette en quartz. CCL22 (1,5 μΜ (tampon HEPES sans albumine) dans 1 mL volume final) est excitée à 285 nm and son spectre d'émission est enregistré entre 300 et 400 nm après chaque ajout d'un aliquot de molécule à tester (1 uL) . Les mesures sont effectuées à 20°C et les solutions sont agitées à l'aide d'un barreau magnétique. Les spectres d'émission enregistré »s sont corrigés par soustraction du spectre d'émission du composés à tester seul. La figure 4 indique qu'une extinction de fluorescence de CCL22 est observée uniquement avec le neutraligand (GPN 136) et non pas avec l'antagoniste du récepteur (C-021) . L'allure de la courbe de titration de CCL22 (1,5 μΜ) par GPN 136 est biphasique, indiquant la présence vraisemblable de plusieurs sites de liaison pour GPN 136, dont un au moins est de haute affinité. L'ajustement des traces par l' équation (RL) 2+ (RL) χ (-Ro-Lo-KD) +Ro*Lo=0 avec (RL) = ( (Ro+Lo+KD) ± ( (-Ro- Lo-KD)2 -4xRo*Lo) 1 2) /2 permet d'estimer l'affinité pour chaque site : KD< 50 nM pour le site de haute affinité et KD= 53μ . This measurement is carried out as described in Hachet-Haas et al. (Small neutralizing molecules to inhibit actions of the chemokine CXCL12, J Biol Chem, 2008, 283 (34), 23189-99). Briefly, the fluorescence measurements are carried out on a Fluorolog 3 spectrofluorometer (JobinYvon / Spex) in a quartz cuvette. CCL22 (1.5 μl (HEPES buffer without albumin) in 1 mL final volume) is excited at 285 nm and its emission spectrum is recorded between 300 and 400 nm after each addition of a test molecule aliquot (1 μL). ). The measurements are carried out at 20 ° C. and the solutions are stirred using a magnetic bar. The recorded emission spectra are corrected by subtracting the emission spectrum of the test compound alone. Figure 4 indicates that fluorescence quenching of CCL22 is observed only with the neutraligand (GPN 136) and not with the receptor antagonist (C-021). The shape of the titration curve of CCL22 (1.5 μΜ) by GPN 136 is biphasic, indicating the probable presence of several GPN binding sites 136, at least one of which is of high affinity. The adjustment of the traces by the equation (RL) 2 + (RL) χ (-Ro-Lo-KD) + Ro * Lo = 0 with (RL) = ((Ro + Lo + KD) ± ((-Ro) - Lo-KD) 2 -4xRo * Lo) 1 2 ) / 2 makes it possible to estimate the affinity for each site: KD <50 nM for the high affinity site and KD = 53μ.
Il n'y a pas de signal pour la molécule C-021. La figure 4 montre l'inhibition de la fluorescence intrinsèque de CCL22 par le neutraligand GPN 136 (carrés blancs). L'antagoniste du récepteur CCR4, C-021, ne présente pas une diminution de fluorescence du tryptophane (carrés noirs) . There is no signal for the C-021 molecule. Figure 4 shows the inhibition of the intrinsic fluorescence of CCL22 by the neutraligand GPN 136 (white squares). The CCR4 receptor antagonist, C-021, does not show a decrease in tryptophan fluorescence (black squares).
L'exemple 5 permet de montrer comment sont sélectionnés les candidats actifs non cytotoxiques. Example 5 shows how non-cytotoxic active candidates are selected.
Exemple 5 : Example 5
Propriétés des dérivés sur la migration de kératinocytes et cytotoxicité Properties of derivatives on keratinocyte migration and cytotoxicity
L'activité de la molécule GPN 136 a été évaluée dans un essai de migration de kératinocytes humains réalisé selon un test de cicatrisation d'un tapis cellulaire. Il est effectivement connu que, dans ces pathologies chroniques, une migration importante des cellules peut favoriser la formation de prurit, une des manifestations de la dermatose. Les kératinocytes humains immortalisés obtenus auprès du DKFZ (Heidelberg, Allemagne) sont cultivés dans du milieu de Dulbecco modifié par Eagle (DMEM, InVitrogen) complémenté par 10% de sérum de veau fœtal (Gibco-BRL) et 100 U/ml de pénicilline ( Invitrogen) , 100 μς/ml de streptomycine ( Invitrogen) and 2 mM L glutamine ( Invitrogen) à 37°C et 5% C02. Les puits d'une plaque de culture 24 puits sont ensemencés avec 200.000 cellules et la culture est maintenue jusqu'à formation d'un tapis confluent. Le tapis est alors endommagé en effectuant un grattage linéaire à l'aide pointe de pipette stérile de 0.1-10μΙ. Le milieu est alors remplacé pour éliminer les cellules et leurs débris et la culture est poursuivie dans différentes conditions expérimentales : (i) sans aucun ajout, (ii) ajout de 100 ng/ml de CCL22 et (iii) ajout d'un mélange contenant 100 ng/ml de CCL22 et la molécule à tester, par exemple GPN 136. L'effet des molécules seules est aussi enregistré dans des puits différents. Afin de bloquer la prolifération cellulaire, chaque puits reçoit une dose de ^g/ml de mytomycine (Sigma- Aldrich) . Les plaques de culture sont disposées dans l'appareil IncuCyte qui enregistre la croissance du tapis cellulaire par imagerie transmise en conditions de culture cellulaire (37°C, 5%C02, atmosphère saturée d' eau) pendant 72h. des images en contraste de phase sont acquise chaque 2 heures. La cicatrisation est définie (quantifiée) comme le rapport de largeur de la cicatrice au temps t par rapport au temps 0. L'expérience est répétée trois fois par condition. Les résultats obtenus sont rapportés dans la figure 5. The activity of the GPN 136 molecule was evaluated in a human keratinocyte migration test carried out according to a cell-wall healing test. It is indeed known that, in these chronic pathologies, a significant migration of cells can promote the formation of pruritus, one of the manifestations of dermatitis. The immortalized human keratinocytes obtained from DKFZ (Heidelberg, Germany) are cultured in Eagle-modified Dulbecco's medium (DMEM, InVitrogen) supplemented with 10% fetal calf serum (Gibco-BRL) and 100 U / ml penicillin ( Invitrogen), 100 μg / ml streptomycin (Invitrogen) and 2 mM glutamine (Invitrogen) at 37 ° C and 5% CO2. The wells of a 24-well culture plate are inoculated with 200,000 cells and the culture is maintained until a confluent mat is formed. The carpet is then damaged by performing a linear scraping using sterile 0.1-10μΙ pipette tip. The medium is then replaced to remove the cells and their debris and the culture is continued under different experimental conditions: (i) without any addition, (ii) addition of 100 ng / ml of CCL22 and (iii) addition of a mixture containing 100 ng / ml of CCL22 and the molecule to be tested, for example GPN 136. The effect of single molecules is also recorded in different wells. In order to block cell proliferation, each well receives a dose of 1 g / ml of mytomycin (Sigma-Aldrich). The culture plates are placed in the IncuCyte apparatus which records the growth of the cell layer by imaging transmitted under cell culture conditions (37 ° C, 5% CO2, saturated atmosphere of water) for 72 hours. Phase contrast images are acquired every 2 hours. Healing is defined (quantified) as the ratio of scar width at time t to time 0. The experiment is repeated three times per condition. The results obtained are reported in Figure 5.
La figure 5 montre la migration de keratinocytes humains sous l'effet de GNP136 ; elle montre des photographies des tapis de cellules Hacat humaines après blessure au temps 0 et après 72h de culture en présence d'excipient seul (DMSO, panneau 1), de CCL22 et d'excipient (CCL22+D SO, panneau 2) et de CCL22 et GPN 136 (CCL22+GPN136, panneau 3) Figure 5 shows the migration of human keratinocytes under the effect of GNP136; it shows photographs of human Hacat cell carpets after injury at time 0 and after 72h of culture in the presence of excipient alone (DMSO, panel 1), CCL22 and excipient (CCL22 + D SO, panel 2) and CCL22 and GPN 136 (CCL22 + GPN136, panel 3)
La figure indique que la migration cellulaire est fortement accélérée par la chimiokine CCL22 qui agit sur les récepteurs CCR4 présents dans les cellules Hacat. Cet effet de la chimiokine CCL22 est aboli par la molécule GPN136. Certains composés sont cytotoxiques : exemple de la molécule GPN 025. The figure indicates that cell migration is strongly accelerated by the CCL22 chemokine which acts on CCR4 receptors present in Hacat cells. This effect of the chemokine CCL22 is abolished by the molecule GPN136. Some compounds are cytotoxic: example of the molecule GPN 025.
La figure 6 montre l'effet de la molécule GPN025 ajoutée au jour J0 après blessure du tapis de cellules Hacat. On note que les cellules semblent avoir formé des syncitia après 72h d'incubation. Il est impossible d'en distinguer les contours. La molécule GPN025 endommage les cellules Hacat. Cet effet est quantifié dans l'expérience de d'activité métabolique présentée sur la figure 6. Le test d'activité métabolique est un test colorimétrique (WST-1 assay - Ozyme) reposant sur la mesure de l'activité de l'enzyme mitochondriale succinate-tetrazolium reductase clivant le sel de tétrazolium WST-1 ( (4- [3- (4-Iodophenyl) -2- ( 4-nitrophenyl ) -2H-5-tetrazolio] -1 , 3 benzène disulfonate) ) en un dérivé hydrosoluble, le formazan qui est un colorant absorbant la lumière dans la fenêtre 420-480 nm. Les cellules HaCat sont distribuées à raison de 200.000 cellules par puits dans une plaque de culture à 24 puits, dans un volume final de 500 μL. Elles sont cultivées pendant 24h avant d'ajouter de la mitomycine C (1 g/ml) et le composé à tester. La plaque de culture est incubée pendant 72h à 37°C, 5%C02, en atmosphère saturée d'eau. Le milieu est ensuite remplacé par du milieu frais complémenté de réactif WST-1 puis incubé pendant 2 heures à 37 °C. Les plaques sont agitées pour homogénéiser la couleur dans les puits et l'absorbance est mesurée à 450 nm dans un lecteur de plaques multipuits. Les mesures sont réalisées en triplicats. L'activité enzymatique requérant l'intégrité cellulaire, l'absorbance sera d'autant plus forte que l'état métabolique des cellules est bon. Figure 6 shows the effect of the added GPN025 molecule on day 10 after injury to the Hacat cell mat. It is noted that the cells appear to have formed syncytia after 72 hours of incubation. It is impossible to distinguish the outlines. The molecule GPN025 damages Hacat cells. This effect is quantified in the metabolic activity experiment shown in Figure 6. The metabolic activity test is a colorimetric test (WST-1 assay - Ozyme) based on the measurement of the activity of the mitochondrial enzyme succinate-tetrazolium reductase cleaving the tetrazolium salt WST-1 ((4- [3- (4-Iodophenyl) -2- (4-nitrophenyl) -2H-5-tetrazoloyl-1,3-benzenesulfonate)) to a water-soluble derivative, formazan which is a light-absorbing dye in the 420-480 nm window. The HaCat cells are distributed at a rate of 200,000 cells per well in a 24-well culture plate, in a final volume of 500 μl. They are cultured for 24 hours before adding mitomycin C (1 g / ml) and the test compound. The culture plate is incubated for 72 hours at 37 ° C., 5% CO 2, in a saturated atmosphere of water. The medium is then replaced with fresh medium supplemented with WST-1 reagent and then incubated for 2 hours at 37 ° C. The plates are shaken to homogenize the color in the wells and the absorbance is measured at 450 nm in a multiwell plate reader. The measurements are made in triplicates. The enzymatic activity requiring cellular integrity, the absorbance will be even stronger than the metabolic state of the cells is good.
La figure 7 montre l'activité cytotoxique de GPN136 et de GPN025  Figure 7 shows the cytotoxic activity of GPN136 and GPN025
Activité cytotoxique in vitro : les cultures de cellules HaCat sont traitées avec différentes concentrations de molécule :0,3μΜ (barres gris sombre) 10 μΜ (barres gris clair) ou 30 μΜ (barres blanches) des molécules GPN 136 et GPN 025. L'activité de l'enzyme formazan-réductase mitochondiale est enregistrée à l'aide du substrat chromogène WST-1 qui se transforme en produit coloré, le formazan, détecté à 450 nm. Comme le montre la figure 7, la molécule GPN 136 n'affecte pas l'activité enzymatique. En revanche, la molécule GPN 025 réduit de manière dose- dépendante et significativement le métabolisme cellulaire, révélant ainsi un effet cytotoxique de GPN 025. In vitro cytotoxic activity: HaCat cell cultures are treated with different molecule concentrations: 0.3μΜ (dark gray bars) 10 μΜ (light gray bars) or 30 μΜ (white bars) GPN 136 and GPN 025 molecules. Mitochondial formazan-reductase enzyme activity is recorded using WST-1 chromogenic substrate which turns into colored product, formazan, detected at 450 nm. As shown in FIG. 7, the GPN 136 molecule does not affect the enzymatic activity. In contrast, the GPN 025 molecule reduces in a dependent and significantly cellular metabolism, thus revealing a cytotoxic effect of GPN 025.
Exemple 6 :  Example 6
Cet exemple présente une formulation de la composition selon 1' invention .  This example presents a formulation of the composition according to the invention.
On applique cette composition tous les jours pendant 1 mois sur la peau du visage d'un homme de 20 ans souffrant de dermatite atopique sur l'ensemble du visage; cette application est faite à raison d'environ 2 g/jour pour le visage complet. On constate la disparition progressive totale des zones d'inflammation à la fin du traitement.  This composition is applied every day for 1 month on the skin of the face of a 20-year-old man suffering from atopic dermatitis on the entire face; this application is made at a rate of about 2 g / day for the complete face. The total disappearance of the inflammation zones at the end of the treatment is observed.
On a proposé ci-après des ingrédients pouvant être associés avec les compositions pour application topique afin d'amplifier l'effet ou atteindre des synergies d'action, notamment avec la formulation du présent exemple 6 (les quantités sont données en pourcentage en poids) : a) des ingrédients ayant des propriétés antiinflammatoires couramment utilisés dans les produits cosmétiques notamment le nicotinamide (1 à 4%), l'acide 18 béta glycyrrhétinique (0.01 à 1%), l'alpha bisabolol (0.1 à 1%) ; The following are proposed ingredients that can be combined with the compositions for topical application in order to amplify the effect or achieve action synergies, especially with the formulation of this example 6 (the amounts are given in percentage by weight). : a) ingredients with anti-inflammatory properties commonly used in cosmetic products, in particular nicotinamide (1 to 4%), beta-glycyrrhetinic acid (0.01 to 1%), alpha bisabolol (0.1 to 1%);
b) la glycine ayant un effet apaisant (de 1 à 3%) ; b) glycine having a soothing effect (from 1 to 3%);
c) les micro-particules d'argent (0.1%) qui permettent de réguler, stabiliser la flore microbienne et éviter la surinfection ; c) the silver micro-particles (0.1%) which make it possible to regulate, stabilize the microbial flora and avoid superinfection;
d) un agent anti-adhésion bactérienne pour limiter l'adhésion et la prolifération de Staphylococcus aureus comme le Téflose® de Solabia composé de propanediol, rhamnose, glucose et acide glucuronique (2 à 4%) ; d) a bacterial anti-adhesion agent to limit the adhesion and proliferation of Staphylococcus aureus such as Solabia Teflose® composed of propanediol, rhamnose, glucose and glucuronic acid (2-4%);
e) les insaponifiables de beurre de karité et de tournesol pour renforcer la barrière cutanée et améliorer l'hydratation de la peau. (0.5 à 2%). e) unsaponifiables of shea butter and sunflower to reinforce the skin barrier and improve skin hydration. (0.5 to 2%).
f) un extrait de chicorée de 1 à 3% (comme la Védérine® de Silab) pour le renforcement et la récupération de la barrière cutanée ; f) a 1-3% chicory extract (such as Vederin® from Silab) for strengthening and recovery of the skin barrier;
g) un dérivé d'huile de pépins de framboise et de succinate de vitamine E (Raspberry seed oil/ Tocopheryl succinate/ Aminopropanediol esters) à 1% comme le Vitaskin® E de Solabia ; g) a derivative of raspberry seed oil and vitamin E succinate (1% Raspberry seed oil / Tocopheryl succinate / Aminopropanediol esters) such as Vitaskin® E from Solabia;
h) l' octyldodécyl PCA dosé de 0.5 à 5% pour stimuler la synthèse des lipides épidermiques ; h) octyldodecyl PCA assayed at 0.5 to 5% to stimulate epidermal lipid synthesis;
i) une huile végétale de carthame ou onagre stabilisée sous une forme céramide-like comme l' »Omega β Ceramide® Safflower » et l' »Omega 6 Ceramide® Evening primrose » de Solabia pour améliorer la cohésion cellulaire (0.1 àl%) ; j ) un mélange optimisé d'huile d'argan, de beurre de karité et de cire d'orge, comme dans le « Stimutex® AS » de DSM, pour une action anti-inflammatoire et pour diminuer la libération d'histamine (2 à 5%); k) un mélange d'extrait d'écorce de bouleau blanc et de Scrophularia nodosa, comme dans le Protectol® de Greentech, pour ses propriétés anti-inflammatoires du fait de la présence d'acide bétulinique (1 et 3%); i) a safflower or evening primrose vegetable oil stabilized in a ceramide-like form such as "Omega β Ceramide® Safflower" and "Omega 6 Ceramide® Evening primrose" from Solabia to improve cell cohesion (0.1 to 1%); j) an optimized blend of argan oil, shea butter and barley wax, as in DSM's Stimutex® AS, for anti-inflammatory action and to decrease histamine release (2). at 5%); k) a mixture of white birch bark extract and Scrophularia nodosa, as in Greentech Protectol®, for its anti-inflammatory properties due to the presence of betulinic acid (1 and 3%);
1) un mélange de lactose et de protéine de lait à 0.5% comme dans le Modukine™ de CLR pour ses propriétés antiinflammatoires .  1) a mixture of lactose and 0.5% milk protein as in CLR Modukine ™ for its anti-inflammatory properties.

Claims

REVENDICATIONS
1. Utilisation d'une composition dermo-cosmétique ou pharmaceutique pour inhiber les chimiokines et traiter des maladies inflammatoires de la peau humaine ou animale, caractérisée en ce que ladite composition contient, dans un véhicule acceptable, une quantité efficace d'au moins un agent actif constitué par un composé répondant à la formule générale (I) : 1. Use of a dermo-cosmetic or pharmaceutical composition for inhibiting chemokines and treating inflammatory diseases of human or animal skin, characterized in that said composition contains, in an acceptable vehicle, an effective amount of at least one agent active compound consisting of a compound corresponding to the general formula (I):
formule dans laquelle : formula in which:
X représente un groupe -CH- ou un atome d'azote ;  X represents a group -CH- or a nitrogen atom;
R représente un groupe {Ci-C&) alkyle, (C3-C6) cycloalkyle, dans lesquels un ou plusieurs groupements -CH2- peuvent être remplacés par -0- ou peuvent être substitués par un ou plusieurs groupes choisis parmi les radicaux (Ci-C6) alkyle, hydroxy et alcoxy, ledit composé de formule (I) pouvant être sous forme de sel. R represents a (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl group, in which one or more -CH 2 - groups may be replaced by -O- or may be substituted by one or more groups selected from radicals; (Ci-C 6) alkyl, hydroxy and alkoxy, said compound of formula (I) may be in salt form.
2. Utilisation selon la revendication 1, caractérisée en ce que, la composition mise en œuvre comporte au moins un composé de formule (I), dans lequel le (ou les) radical (aux) alkyle est (sont) choisi (s) dans le groupe formé par les radicaux méthyle, propyle, isopropyle, butyle, isobutyle, tertiobutyle, pentyle, néopentyle, n-hexyle substitué (s) ou non par un ou plusieurs groupement (s) hydroxyle ou par un ou plusieurs groupement (s) alcoxy.  2. Use according to claim 1, characterized in that the composition used comprises at least one compound of formula (I), in which the alkyl radical (s) is (are) chosen from the group formed by the methyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl or n-hexyl radicals, which may or may not be substituted by one or more hydroxyl groups or by one or more alkoxy group (s); .
3. Utilisation selon l'une des revendications 1 à 2, caractérisée en ce que, lorsque la composition mise en œuvre comporte au moins un composé de formule (I), dont le radical R est un radical cycloalkyle, ledit radical R est mono ou polycyclique, notamment cyclopropyle ou cyclohexyle. 3. Use according to one of claims 1 to 2, characterized in that, when the composition used comprises at least one compound of formula (I), the radical R of which is a cycloalkyl radical, said radical R is mono or polycyclic, in particular cyclopropyl or cyclohexyl.
4. Utilisation selon l'une des revendications 1 à 3, caractérisée en ce que, lorsque la composition mise en œuvre contient au moins un composé de formule (I) comportant au moins un radical alcoxy, ledit radical alcoxy est choisi dans le groupe formé par les groupes méthoxy, éthoxy, n- propyloxy, i-propyloxy, ii-butoxy, s-butoxy, t-butoxy, n- pentoxy et s-pentoxy, chaque groupe alcoxy pouvant être substitué par un radical alkyle tel que défini dans la revendication 2.  4. Use according to one of claims 1 to 3, characterized in that, when the composition used contains at least one compound of formula (I) comprising at least one alkoxy radical, said alkoxy radical is chosen from the group formed methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy and s-pentoxy, each alkoxy group being substituted with an alkyl radical as defined in claim 2.
5. Utilisation selon la revendication 1, caractérisée en ce que, dans la composition mise en œuvre, l'agent actif est un sel d'addition acide, ledit acide étant choisi dans le groupe formé par les acides chlorhydrique, bromhydrique, sulfurique phosphorique , acétique, trifluoacétique, lactique, pyruvique, malonique, succinique, glutarique, fumarique, tartrique, maléique, citrique, ascorbique, méthane- ou éthane-sulfonique et camphorique.  5. Use according to claim 1, characterized in that, in the composition used, the active agent is an acid addition salt, said acid being selected from the group consisting of hydrochloric, hydrobromic, sulfuric phosphoric acid, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methane- or ethanesulfonic and camphoric.
6. Utilisation selon la revendication, caractérisée en ce que, dans la composition mise en œuvre, l'agent actif est un sel d'addition basique, ladite base étant choisie dans le groupe formé par l'hydroxyde de sodium ou de potassium, la triéthylamine et la tertiobutylamine.  6. Use according to the claim, characterized in that, in the composition used, the active agent is a basic addition salt, said base being selected from the group consisting of sodium hydroxide or potassium hydroxide, the triethylamine and tert-butylamine.
7. Utilisation selon la revendication 1, caractérisée en ce que la composition mise en œuvre contient comme agent actif un composé.- de formule (I), ledit composé étant choisi dans le groupe formé par  7. Use according to claim 1, characterized in that the composition used contains as active agent a compound of formula (I), said compound being chosen from the group formed by
2, 3-dihydroxypropyl 2-hydroxybenzoate  2,3-dihydroxypropyl 2-hydroxybenzoate
(S) -2, 3-dihydroxypropyl 2-hydroxybenzoate  (S) -2,3-dihydroxypropyl 2-hydroxybenzoate
(R) -2, 3-dihydroxypropyl 2-hydroxybenzoate 2 , 3-dihydroxypropyl 4-hydroxynicotinate et ses isomères dipropylene glycol salicylate et ses isomères (R) -2,3-dihydroxypropyl 2-hydroxybenzoate 2,3-dihydroxypropyl 4-hydroxynicotinate and its isomers dipropylene glycol salicylate and its isomers
propylene glycol salicylate et ses isomères propylene glycol salicylate and its isomers
8. Utilisation selon l'une des revendications 1 à 7, caractérisée en ce que la composition mise en oeuvre contient de 0,01 à 5% en poids d'agent (s) actif (s) de formule (I) par rapport au poids total de la composition.  8. Use according to one of claims 1 to 7, characterized in that the composition used contains 0.01 to 5% by weight of active agent (s) of formula (I) relative to total weight of the composition.
9. Utilisation selon l'une des revendications 1 à 8, caractérisée en ce que le (ou les) agents actifs de formule (I) de la composition mise en œuvre est (sont) sous forme de poudre, ou sont absorbés sur des polymères organiques poudreux, notamment talcs ou bentonites, ou sont sous forme encapsulée.  9. Use according to one of claims 1 to 8, characterized in that the (or) active agents of formula (I) of the composition used is (are) in the form of powder, or are absorbed on polymers organic powdery, especially talcs or bentonites, or are in encapsulated form.
10. Utilisation selon la revendication 9, caractérisée en ce que lorsqu'un agent actif de formule (I) de la composition mise en œuvre est (sont) sous forme encapsulée, son (ou ses) moyen (s) d' encapsulation est (ou sont) choisi (s) dans le groupe formé par des microsphères, des liposomes, des glycosphères, des chylomicrons, des macro- micro-, , et nanoparticules , des macro-, micro- et nanocapsules .  10. Use according to claim 9, characterized in that when an active agent of formula (I) of the composition used is (are) in encapsulated form, its (or its) means (s) of encapsulation is ( or are) selected from the group consisting of microspheres, liposomes, glycospheres, chylomicrons, macro-micro-, and nanoparticles, macro-, micro- and nanocapsules.
11. Utilisation selon l'une des revendications 1 à 10, caractérisée en ce que la composition mise en œuvre contient au moins un agent actif complémentaire autre qu'un composé de formule (I), ledit agent complémentaire étant pris dans le groupe formé par les agents de protection solaire, les agents antirides à activité antiradicalaire, antioxydante, anti-irritante, les agents favorisant la nutrition cellulaire, la respiration cellulaire, l'hydratation cellulaire, la régénération cellulaire, les traitements anti-séborrhéiques, la tonicité cutanée, la protection des cheveux, les agents cicatrisants, l'acide hyaluronique, les acides aminés, les agents anti-âge et les agents après- soleil. 11. Use according to one of claims 1 to 10, characterized in that the composition used contains at least one additional active agent other than a compound of formula (I), said additional agent being taken from the group formed by sunscreen agents, anti-wrinkle agents with anti-radical activity, anti-oxidant, anti-irritant, agents promoting cell nutrition, cellular respiration, cellular hydration, cellular regeneration, anti-seborrhoeic treatments, cutaneous tonicity, hair protection, healing agents, hyaluronic acid, amino acids, anti-aging agents and Sun.
12. Utilisation selon l'une des revendications 1 à 11, caractérisée en ce la composition mise en œuvre est formulée sous forme de lotion, gel, émulsion, crème ou lait, émulsion bi-phasique huile dans eau ou eau dans huile, émulsion tri- phasique, huile corporelle, shampoing, savon, masque, onguent, pommade et crayon pour maquillage, bâton protecteur des lèvres, nanocapsule, liposome ou patch transdermique pour applications topiques.  12. Use according to one of claims 1 to 11, characterized in that the composition used is formulated in the form of lotion, gel, emulsion, cream or milk, two-phase emulsion oil in water or water in oil, emulsion sorting - Phasic, body oil, shampoo, soap, mask, ointment, ointment and pencil for makeup, lipstick, nanocapsule, liposome or transdermal patch for topical applications.
13. Utilisation selon l'une des revendications 1 à 12, caractérisée en ce que la composition mise en oeuvre contient au moins un produit pris dans le groupe formé par des mucopolysaccharides , des vitamines, des céramides, des huiles végétales et des agents efficaces dans les dermatoses.  13. Use according to one of claims 1 to 12, characterized in that the composition used contains at least one product taken from the group consisting of mucopolysaccharides, vitamins, ceramides, vegetable oils and agents effective in dermatoses.
14. Utilisation selon l'une des revendications 1 à 13, caractérisée en ce que la composition mise en oeuvre contient au moins un produit pris dans le groupe formé par des agents antibactériens, des parfums, des lipides d'extraction et/ou de synthèse, des polymères gélifiants et viscosants, des tensio-actifs , des émulsifiants, des extraits de plantes, des extraits tissulaires, des extraits marins, des actifs hydro- ou lipo-solubles , des actifs de synthèse .  14. Use according to one of claims 1 to 13, characterized in that the composition used contains at least one product taken from the group consisting of antibacterial agents, perfumes, lipids extraction and / or synthesis , gelling and viscosity polymers, surfactants, emulsifiers, plant extracts, tissue extracts, marine extracts, hydro- or liposoluble active agents, synthetic active agents.
15. Utilisation selon l'une des revendications 1 à 14, caractérisée en ce que la composition mise en oeuvre est administrable par voie topique ou orale.  15. Use according to one of claims 1 to 14, characterized in that the composition used is administrable topically or orally.
16. Utilisation d'une composition selon la revendication 16, pour traiter des maladies inflammatoires chroniques soit externes, notamment les dermatoses, l'acné, la dermatite atopique, le psoriasis, l'eczéma, la sécheresse de peau à tendance atopique, les rougeurs de la peau, soit internes, notamment la maladie de Crohn, l'asthme, l'asthme allergique et la rhinite allergique. 16. Use of a composition according to claim 16, for treating chronic inflammatory diseases or external diseases, in particular dermatoses, acne, atopic dermatitis, psoriasis, eczema, atopic skin dryness, redness. of the skin, either internal, including Crohn's disease, asthma, allergic asthma and allergic rhinitis.
17. Utilisation d'une composition selon l'une des revendications 1 à 15, sur un sujet animal ou humain, dans le traitement des maladies dermatologiques liées à des activités séborrhéiques, acnéiques, inflammatoires et immunologiques .  17. Use of a composition according to one of claims 1 to 15, on an animal or human subject, in the treatment of dermatological diseases related to seborrheic, acne, inflammatory and immunological activities.
EP15788100.4A 2014-09-24 2015-09-22 Dermocosmetic or pharmaceutical use of a composition containing at least one inhibitor of certain chemokines Active EP3197460B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR1402163A FR3026011B1 (en) 2014-09-24 2014-09-24 COMPOSITION COMPRISING AT LEAST ONE INHIBITOR OF CERTAIN CHEMOKINES, METHOD FOR PRODUCING THE SAME AND USE THEREOF DERMOCOSMAL PHARMACEUTICAL
PCT/FR2015/000185 WO2016046456A1 (en) 2014-09-24 2015-09-22 Dermocosmetic or pharmaceutical use of a composition containing at least one inhibitor of certain chemokines

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EP3197460A1 true EP3197460A1 (en) 2017-08-02
EP3197460B1 EP3197460B1 (en) 2022-04-20

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EP (1) EP3197460B1 (en)
FR (1) FR3026011B1 (en)
WO (1) WO2016046456A1 (en)

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CN106854204B (en) * 2016-11-22 2019-10-08 斯芬克司药物研发（天津）股份有限公司 A kind of niacin compound and the preparation method and application thereof
CN106749210B (en) * 2016-11-22 2019-08-09 斯芬克司药物研发（天津）股份有限公司 A kind of nicotinate compound and the preparation method and application thereof
CN106749211B (en) * 2016-11-22 2019-08-09 斯芬克司药物研发（天津）股份有限公司 A kind of nicotinate and the preparation method and application thereof
CN109422858A (en) * 2017-08-19 2019-03-05 中国铁道科学研究院铁道建筑研究所 A kind of polyalcohol being grafted UV absorption agent molecule

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Publication number Priority date Publication date Assignee Title
US7179476B2 (en) * 2001-08-09 2007-02-20 Sekisui Chemical Co., Ltd. Medical composition for external use for dermatosis
FR2983858B1 (en) * 2011-12-08 2014-01-03 Fabre Pierre Dermo Cosmetique NOVEL INHIBITORY COMPOUNDS OF LIPOGENESIS
WO2014164806A1 (en) * 2013-03-12 2014-10-09 Mary Kay Inc. Preservative system

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See also references of WO2016046456A1 *

Also Published As

Publication number Publication date
EP3197460B1 (en) 2022-04-20
FR3026011B1 (en) 2019-07-19
US20170281653A1 (en) 2017-10-05
FR3026011A1 (en) 2016-03-25
WO2016046456A1 (en) 2016-03-31

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